Science.gov

Sample records for ras design simulation

  1. Design and Performance of McRas in SCMs and GEOS I/II GCMs

    NASA Technical Reports Server (NTRS)

    Sud, Yogesh C.; Einaudi, Franco (Technical Monitor)

    2000-01-01

    The design of a prognostic cloud scheme named McRAS (Microphysics of clouds with Relaxed Arakawa-Schubert Scheme) for general circulation models (GCMs) will be discussed. McRAS distinguishes three types of clouds: (1) convective, (2) stratiform, and (3) boundary-layer types. The convective clouds transform and merge into stratiform clouds on an hourly time-scale, while the boundary-layer clouds merge into the stratiform clouds instantly. The cloud condensate converts into precipitation following the auto-conversion equations of Sundqvist that contain a parametric adaptation for the Bergeron-Findeisen process of ice crystal growth and collection of cloud condensate by precipitation. All clouds convect, advect, as well as diffuse both horizontally and vertically with a fully interactive cloud-microphysics throughout the life-cycle of the cloud, while the optical properties of clouds are derived from the statistical distribution of hydrometeors and idealized cloud geometry. An evaluation of McRAS in a single column model (SCM) with the GATE Phase III and 5-ARN CART datasets has shown that together with the rest of the model physics, McRAS can simulate the observed temperature, humidity, and precipitation without many systematic errors. The time history and time mean incloud water and ice distribution, fractional cloudiness, cloud optical thickness, origin of precipitation in the convective anvil and towers, and the convective updraft and downdraft velocities and mass fluxes all show a realistic behavior. Performance of McRAS in GEOS 11 GCM shows several satisfactory features but some of the remaining deficiencies suggest need for additional research involving convective triggers and inhibitors, provision for continuously detraining updraft, a realistic scheme for cumulus gravity wave drag, and refinements to physical conditions for ascertaining cloud detrainment level.

  2. Rational design of small molecule inhibitors targeting the Ras GEF, SOS1

    PubMed Central

    Evelyn, Chris R.; Duan, Xin; Biesiada, Jacek; Seibel, William L.; Meller, Jaroslaw; Zheng, Yi

    2014-01-01

    Summary Ras GTPases regulate intracellular signaling involved in cell proliferation. Elevated Ras signaling activity has been associated with human cancers. Ras activation is catalyzed by guanine-nucleotide exchange factors (GEFs), of which SOS1 is a major member that transduces receptor tyrosine kinase signaling to Ras. We have developed a rational approach coupling virtual screening with experimental screening in identifying small-molecule inhibitors targeting the catalytic site of SOS1 and SOS1-regulated Ras activity. A lead inhibitor, NSC-658497, is found to bind to SOS1, competitively suppresses SOS1-Ras interaction, and dose-dependently inhibits SOS1 GEF activity. Mutagenesis and structure-activity relationship studies map the NSC-658497 site of action to the SOS1 catalytic site, and define the chemical moieties in the inhibitor essential for the activity. NSC-658497 showed dose-dependent efficacy in inhibiting Ras, downstream signaling activities, and associated cell proliferation. These studies establish a proof of principle for rational design of small-molecule inhibitors targeting Ras GEF enzymatic activity. PMID:25455859

  3. Terahertz Gyrotrons at IAP RAS: Status and New Designs

    NASA Astrophysics Data System (ADS)

    Bratman, V. L.; Glyavin, M. Yu.; Kalynov, Yu. K.; Litvak, A. G.; Luchinin, A. G.; Savilov, A. V.; Zapevalov, V. E.

    2011-03-01

    Powerful gyrotrons with radiation frequencies in the range 0.33-0.65 THz were demonstrated at the IAP as early as in the 1970-1980s. This trend has recently been renewed in connection with a significant increase in interest in terahertz frequency range. In the course of new experiments, the radiation frequency of pulsed gyrotrons was increased up to 1.3 THz and 1 THz at the fundamental and third cyclotron harmonics, respectively. In addition, gyrotrons operated in CW regime with a frequency of 0.3 THz for technological applications (in collaboration with the University of Fukui, Japan) and 0.26 THz for the dynamic nuclear polarization at a high-field NMR were implemented. Designs of a pulsed fundamental-harmonic gyrotron with MW-level power at 0.3 THz and a CW kW-level third-harmonic gyrotron with a frequency of 0.4 THz are currently developed. Estimates show that modern techniques for the creation of strong magnetic fields now make it possible to realize gyrotrons with an operating frequency at least up to 1-1.5 THz. Such generators utilize a relatively low particle energy and can provide higher average power than the existing FELs.

  4. RAS and LES Simulation of the supercritical flow over the waving bed

    NASA Astrophysics Data System (ADS)

    Fu, X.; Ma, H.; Heyman, J.; Mettra, F.; Liu, D.; Ancey, C.

    2013-12-01

    The phenomena of bed forms exist widely in the natural rivers and are still not fully understood. The detailed sediment dynamics near the bed is essential for this problem. However, the fluid dynamics near the bed, which drives the sediment motion, is not clear. In this talk, we focus on the fluid dynamics of supercritical flow over a sinusoidal wavy bed, especially around the wall region. This setup mimics anti-dunes morphology i.e. bedforms that are commonly found in steep mountain streams. In this case, the flow depth and the bedform amplitude have the same order of magnitude with the amplitude of the bedform. To study the detailed fluid flow, a 3-Dimensional numerical simulation of Navier-Stokes equations is performed. Two different models, Reynolds Average Simulation (RAS) and Large Eddy Simulation (LES), are used for the turbulence closure. The two models are validated with experiments carried out on a wavy bed. Particular attention is paid to the fluid shear stress on the wavy bed and the bedform equivalent roughness. LES shows more abilities for this problem. In future, various wavelength and amplitude of the sinus wave will be implemented so that new shear stress formulas and parameterization for the anti-dune roughness in shallow water equations will be proposed.

  5. Designing Simulation Systems

    ERIC Educational Resources Information Center

    Twelker, Paul A.

    1969-01-01

    "The purpose of this paper is to outline the approach to designing instructional simulation systems developed at Teaching Research. The 13 phases of simulation design will be summarized, and an effort will be made to expose the vital decision points that confront the designer as he develops simulation experiences. (Author)

  6. Ras history

    PubMed Central

    2010-01-01

    Although the roots of Ras sprouted from the rich history of retrovirus research, it was the discovery of mutationally activated RAS genes in human cancer in 1982 that stimulated an intensive research effort to understand Ras protein structure, biochemistry and biology. While the ultimate goal has been developing anti-Ras drugs for cancer treatment, discoveries from Ras have laid the foundation for three broad areas of science. First, they focused studies on the origins of cancer to the molecular level, with the subsequent discovery of genes mutated in cancer that now number in the thousands. Second, elucidation of the biochemical mechanisms by which Ras facilitates signal transduction established many of our fundamental concepts of how a normal cell orchestrates responses to extracellular cues. Third, Ras proteins are also founding members of a large superfamily of small GTPases that regulate all key cellular processes and established the versatile role of small GTP-binding proteins in biology. We highlight some of the key findings of the last 28 years. PMID:21686117

  7. Perceptually Augmented Simulator Design.

    PubMed

    Edmunds, T; Pai, D K

    2012-01-01

    Training simulators have proven their worth in a variety of fields, from piloting to air-traffic control to nuclear power station monitoring. Designing surgical simulators, however, poses the challenge of creating trainers that effectively instill not only high-level understanding of the steps to be taken in a given situation, but also the low-level "muscle-memory" needed to perform delicate surgical procedures. It is often impossible to build an ideal simulator that perfectly mimics the haptic experience of a surgical procedure, but by focussing on the aspects of the experience that are perceptually salient we can build simulators that effectively instill learning. We propose a general method for the design of surgical simulators that augment the perceptually salient aspects of an interaction. Using this method, we can increase skill-transfer rates without requiring expensive improvements in the capability of the rendering hardware or the computational complexity of the simulation. In this paper, we present our decomposition-based method for surgical simulator design, and describe a user-study comparing the training effectiveness of a haptic-search-task simulator designed using our method versus an unaugmented simulator. The results show that perception-based task decomposition can be used to improve the design of surgical simulators that effectively impart skill by targeting perceptually significant aspects of the interaction. PMID:26963831

  8. Design, dimensioning, and performance of a research facility for studies on the requirements of fish in RAS environments

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Recirculating aquaculture systems (RAS) are increasingly being used for Atlantic salmon smolt production. However, knowledge of how the RAS environment affects welfare and performance of Atlantic salmon is limited. For instance, safe limits for chronic exposure to typical compounds in RAS, such as N...

  9. RAS diseases in children

    PubMed Central

    Niemeyer, Charlotte M.

    2014-01-01

    RAS genes encode a family of 21 kDa proteins that are an essential hub for a number of survival, proliferation, differentiation and senescence pathways. Signaling of the RAS-GTPases through the RAF-MEK-ERK pathway, the first identified mitogen-associated protein kinase (MAPK) cascade is essential in development. A group of genetic syndromes, named “RASopathies”, had been identified which are caused by heterozygosity for germline mutations in genes that encode protein components of the RAS/MAPK pathway. Several of these clinically overlapping disorders, including Noonan syndrome, Noonan-like CBL syndrome, Costello syndrome, cardio-facio-cutaneous (CFC) syndrome, neurofibromatosis type I, and Legius syndrome, predispose to cancer and abnormal myelopoiesis in infancy. This review focuses on juvenile myelomonocytic leukemia (JMML), a malignancy of early childhood characterized by initiating germline and/or somatic mutations in five genes of the RAS/MAPK pathway: PTPN11, CBL, NF-1, KRAS and NRAS. Natural courses of these five subtypes differ, although hematopoietic stem cell transplantation remains the only curative therapy option for most children with JMML. With whole-exome sequencing studies revealing few secondary lesions it will be crucial to better understand the RAS/MAPK signaling network with its crosstalks and feed-back loops to carefully design early clinical trials with novel pharmacological agents in this still puzzling leukemia. PMID:25420281

  10. Rational design of point mutation-selective antisense DNA targeted to codon 12 of Ha-ras mRNA in human cells.

    PubMed Central

    Duroux, I; Godard, G; Boidot-Forget, M; Schwab, G; Hélène, C; Saison-Behmoaras, T

    1995-01-01

    Antisense oligodeoxynucleotides targeted to Ha-ras mRNA have been designed to discriminate between the codon 12-mutated oncogene and the normal proto-oncogene. An in vitro assay using two different sources of RNase H (rabbit reticulocyte lysates and nuclear extract from HeLa cells) was used to characterize oligonucleotide binding to normal and mutated Ha-ras mRNA. Short oligonucleotides (12- or 13mers) centered on the mutation had a very high discriminatory efficiency. Longer oligonucleotides (16mers) did not discriminate efficiently between the mutated and the normal mRNA. We have tested the efficacy of dodecanucleotides to induce RNase H cleavage of the full-length mRNA, moving the target sequence from the loop to the stem region which is formed in the vicinity of mutated codon 12. The most selective oligonucleotides were centered on the mutation which is located near the junction between the loop and stem regions even though they were less efficient at inducing RNase H cleavage than those targeted to the loop region. The 12mer antisense oligonucleotide with the highest discriminatory power was selected for cell culture studies. This oligonucleotide inhibited the proliferation of a human cell line which had been transformed with the mutated Ha-ras gene (HBL100ras1) but had no effect on the parental cell line which was transfected with the vector DNA (HBL 100neo) and expressed only the normal Ha-ras gene. Growth inhibition of HBL100ras1 cells was associated with specific ablation of targeted Ha-ras mRNA as shown by RT-PCR. These results show that 'in vitro' evaluation using an RNase H assay allowed us to select an antisense oligonucleotide which elicited a selectivity towards point-mutated Ha-ras mRNA when added at 10 microM concentration to the culture medium of cells expressing wild type and mutated Ha-ras mRNA. Images PMID:7567450

  11. RAS Laboratory Groups

    Cancer.gov

    The RAS Initiative uses multiple technologies to attack RAS-driven cancers. The resources of the Frederick National Lab allocated to the RAS Hub are organized into seven laboratory groups, each contributing to the collaborative effort.

  12. The RAS Initiative

    Cancer.gov

    NCI established the RAS Initiative to explore innovative approaches for attacking the proteins encoded by mutant forms of RAS genes and to ultimately create effective, new therapies for RAS-related cancers.

  13. Combined Rational Design and a High Throughput Screening Platform for Identifying Chemical Inhibitors of a Ras-activating Enzyme*

    PubMed Central

    Evelyn, Chris R.; Biesiada, Jacek; Duan, Xin; Tang, Hong; Shang, Xun; Papoian, Ruben; Seibel, William L.; Nelson, Sandra; Meller, Jaroslaw; Zheng, Yi

    2015-01-01

    The Ras family small GTPases regulate multiple cellular processes, including cell growth, survival, movement, and gene expression, and are intimately involved in cancer pathogenesis. Activation of these small GTPases is catalyzed by a special class of enzymes, termed guanine nucleotide exchange factors (GEFs). Herein, we developed a small molecule screening platform for identifying lead hits targeting a Ras GEF enzyme, SOS1. We employed an ensemble structure-based virtual screening approach in combination with a multiple tier high throughput experimental screen utilizing two complementary fluorescent guanine nucleotide exchange assays to identify small molecule inhibitors of GEF catalytic activity toward Ras. From a library of 350,000 compounds, we selected a set of 418 candidate compounds predicted to disrupt the GEF-Ras interaction, of which dual wavelength GDP dissociation and GTP-loading experimental screening identified two chemically distinct small molecule inhibitors. Subsequent biochemical validations indicate that they are capable of dose-dependently inhibiting GEF catalytic activity, binding to SOS1 with micromolar affinity, and disrupting GEF-Ras interaction. Mutagenesis studies in conjunction with structure-activity relationship studies mapped both compounds to different sites in the catalytic pocket, and both inhibited Ras signaling in cells. The unique screening platform established here for targeting Ras GEF enzymes could be broadly useful for identifying lead inhibitors for a variety of small GTPase-activating GEF reactions. PMID:25825487

  14. Design, Evaluation and GCM-Performance of a New Parameterization for Microphysics of Clouds with Relaxed Arakawa-Schubert Scheme (McRas)

    NASA Technical Reports Server (NTRS)

    Sud, Y. C.; Walker, G. K.

    1998-01-01

    A prognostic cloud scheme named McRAS (Microphysics of clouds with Relaxed Arakawa-Schubert Scheme) was developed with the aim of improving cloud-microphysics, and cloud-radiation interactions in GCMs. McRAS distinguishes convective, stratiform, and boundary-layer clouds. The convective clouds merge into stratiform clouds on an hourly time-scale, while the boundary-layer clouds do so instantly. The cloud condensate transforms into precipitation following the auto-conversion relations of Sundqvist that contain a parametric adaptation for the Bergeron-Findeisen process of ice crystal growth and collection of cloud condensate by precipitation. All clouds convect, advect, and diffuse both horizontally and vertically with a fully active cloud-microphysics throughout its life-cycle, while the optical properties of clouds are derived from the statistical distribution of hydrometeors and idealized cloud geometry. An evaluation of McRAS in a single column model (SCM) with the GATE Phase III data has shown that McRAS can simulate the observed temperature, humidity, and precipitation without discernible systematic errors. An evaluation with the ARM-CART SCM data in a cloud model intercomparison exercise shows reasonable but not an outstanding accurate simulation. Such a discrepancy is common to almost all models and is related, in part, to the input data quality. McRAS was implemented in the GEOS II GCM. A 50 month integration that was initialized with the ECMWF analysis of observations for January 1, 1987 and forced with the observed sea-surface temperatures and sea-ice distribution and vegetation properties (biomes, and soils), with prognostic soil moisture, snow-cover, and hydrology showed a very realistic simulation of cloud process, incloud water and ice, and cloud-radiative forcing (CRF). The simulated ITCZ showed a realistic time-mean structure and seasonal cycle, while the simulated CRF showed sensitivity to vertical distribution of cloud water which can be easily

  15. Backbone conformational flexibility of the lipid modified membrane anchor of the human N-Ras protein investigated by solid-state NMR and molecular dynamics simulation.

    PubMed

    Vogel, Alexander; Reuther, Guido; Roark, Matthew B; Tan, Kui-Thong; Waldmann, Herbert; Feller, Scott E; Huster, Daniel

    2010-02-01

    The lipid modified human N-Ras protein, implicated in human cancer development, is of particular interest due to its membrane anchor that determines the activity and subcellular location of the protein. Previous solid-state NMR investigations indicated that this membrane anchor is highly dynamic, which may be indicative of backbone conformational flexibility. This article aims to address if a dynamic exchange between three structural models exist that had been determined previously. We applied a combination of solid-state nuclear magnetic resonance (NMR) methods and replica exchange molecular dynamics (MD) simulations using a Ras peptide that represents the terminal seven amino acids of the human N-Ras protein. Analysis of correlations between the conformations of individual amino acids revealed that Cys 181 and Met 182 undergo collective conformational exchange. Two major structures constituting about 60% of all conformations could be identified. The two conformations found in the simulation are in rapid exchange, which gives rise to low backbone order parameters and nuclear spin relaxation as measured by experimental NMR methods. These parameters were also determined from two 300 ns conventional MD simulations, providing very good agreement with the experimental data. PMID:19819220

  16. Hydro/Engineering Geophysical Parameters and Design Response Spectrum for Sustainable Development in Ras Muhammed National Park, Sinai

    NASA Astrophysics Data System (ADS)

    Khalil, Mohamed H.; Gamal, Mohamed A.

    2016-01-01

    The Egyptian government is preparing a sustainable development master plan for the Ras Muhammed National Park (RMNP), south Sinai. Noteworthy, the scarcity of the freshwater resources and close proximity to the active seismic zones of the Gulf of Aqaba implicate geophysical investigations for the fresh groundwater aquifers and construct a design response spectrum, respectively. Accordingly, 14 VESs, hydro/engineering geophysical analysis, pumping tests, downhole seismic test, a design response spectrum for buildings, and borehole data were carried out in the study area. The unconfined freshwater aquifer was effectively depicted with true resistivities, thickness, and EC ranged from 56 to 135 Ω m, 11 to 112 m, and 1.4 to 7.1 mS/m, respectively. The Northeastern part was characterized by higher aquifer potentiality, where coarser grains size, highest thickness (112 m), high true resistivity (135 Ω m), groundwater flow (0.074 m3/day), tortuosity (1.293-1.312), formation resistivity factor (4.1-4.6), and storativity (0.281-0.276). An increase in pumping rate was accompanied by an increase in well loss, increase in aquifer losses, decrease in well specific capacity, and decrease in well efficiency. Design response spectrum prognosticated the short buildings (<7 floors) in RMNP to be suffering from a high peak horizontal acceleration and shear forces for acceleration between 0.25 and 0.35 g. Therefore, appropriate detailing of shear reinforcement is indispensable to reduce the risk of structural damages at RMNP.

  17. Hydro/Engineering Geophysical Parameters and Design Response Spectrum for Sustainable Development in Ras Muhammed National Park, Sinai

    NASA Astrophysics Data System (ADS)

    Khalil, Mohamed H.; Gamal, Mohamed A.

    2016-06-01

    The Egyptian government is preparing a sustainable development master plan for the Ras Muhammed National Park (RMNP), south Sinai. Noteworthy, the scarcity of the freshwater resources and close proximity to the active seismic zones of the Gulf of Aqaba implicate geophysical investigations for the fresh groundwater aquifers and construct a design response spectrum, respectively. Accordingly, 14 VESs, hydro/engineering geophysical analysis, pumping tests, downhole seismic test, a design response spectrum for buildings, and borehole data were carried out in the study area. The unconfined freshwater aquifer was effectively depicted with true resistivities, thickness, and EC ranged from 56 to 135 Ω m, 11 to 112 m, and 1.4 to 7.1 mS/m, respectively. The Northeastern part was characterized by higher aquifer potentiality, where coarser grains size, highest thickness (112 m), high true resistivity (135 Ω m), groundwater flow (0.074 m3/day), tortuosity (1.293-1.312), formation resistivity factor (4.1-4.6), and storativity (0.281-0.276). An increase in pumping rate was accompanied by an increase in well loss, increase in aquifer losses, decrease in well specific capacity, and decrease in well efficiency. Design response spectrum prognosticated the short buildings (<7 floors) in RMNP to be suffering from a high peak horizontal acceleration and shear forces for acceleration between 0.25 and 0.35 g. Therefore, appropriate detailing of shear reinforcement is indispensable to reduce the risk of structural damages at RMNP.

  18. SUMO wrestling with Ras

    PubMed Central

    Zhang, Haibo; Luo, Ji

    2016-01-01

    ABSTRACT This review discusses our current understanding of the small ubiquitin-like modifier (SUMO) pathway and how it functionally intersects with Ras signaling in cancer. The Ras family of small GTPases are frequently mutated in cancer. The role of the SUMO pathway in cancer and in Ras signaling is currently not well understood. Recent studies have shown that the SUMO pathway can both regulate Ras/MAPK pathway activity directly and support Ras-driven oncogenesis through the regulation of proteins that are not direct Ras effectors. We recently discovered that in Ras mutant cancer cells, the SUMOylation status of a subset of proteins is altered and one such protein, KAP1, is required for Ras-driven transformation. A better understanding of the functional interaction between the SUMO and Ras pathways could lead to new insights into the mechanism of Ras-driven oncogenesis. PMID:27057691

  19. Inhibitors of Ras-SOS Interactions.

    PubMed

    Lu, Shaoyong; Jang, Hyunbum; Zhang, Jian; Nussinov, Ruth

    2016-04-19

    Activating Ras mutations are found in about 30 % of human cancers. Ras activation is regulated by guanine nucleotide exchange factors, such as the son of sevenless (SOS), which form protein-protein interactions (PPIs) with Ras and catalyze the exchange of GDP by GTP. This is the rate-limiting step in Ras activation. However, Ras surfaces lack any evident suitable pockets where a molecule might bind tightly, rendering Ras proteins still 'undruggable' for over 30 years. Among the alternative approaches is the design of inhibitors that target the Ras-SOS PPI interface, a strategy that is gaining increasing recognition for treating Ras mutant cancers. Herein we focus on data that has accumulated over the past few years pertaining to the design of small-molecule modulators or peptide mimetics aimed at the interface of the Ras-SOS PPI. We emphasize, however, that even if such Ras-SOS therapeutics are potent, drug resistance may emerge. To counteract this development, we propose "pathway drug cocktails", that is, drug combinations aimed at parallel (or compensatory) pathways. A repertoire of classified cancer, cell/tissue, and pathway/protein combinations would be beneficial toward this goal. PMID:26630662

  20. Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP.

    PubMed

    Garcia, Lia C; Donadío, Lucia Gandolfi; Mann, Ella; Kolusheva, Sofiya; Kedei, Noemi; Lewin, Nancy E; Hill, Colin S; Kelsey, Jessica S; Yang, Jing; Esch, Timothy E; Santos, Marina; Peach, Megan L; Kelley, James A; Blumberg, Peter M; Jelinek, Raz; Marquez, Victor E; Comin, Maria J

    2014-06-15

    The development of selective agents capable of discriminating between protein kinase C (PKC) isoforms and other diacylglycerol (DAG)-responsive C1 domain-containing proteins represents an important challenge. Recent studies have highlighted the role that Ras guanine nucleotide-releasing protein (RasGRP) isoforms play both in immune responses as well as in the development of prostate cancer and melanoma, suggesting that the discovery of selective ligands could have potential therapeutic value. Thus far, the N-methyl-substituted indololactone 1 is the agonist with the highest reported potency and selectivity for RasGRP relative to PKC. Here we present the synthesis, binding studies, cellular assays and biophysical analysis of interactions with model membranes of a family of regioisomers of 1 (compounds 2-5) that differ in the position of the linkage between the indole ring and the lactone moiety. These structural variations were studied to explore the interaction of the active complex (C1 domain-ligand) with cellular membranes, which is believed to be an important factor for selectivity in the activation of DAG-responsive C1 domain containing signaling proteins. All compounds were potent and selective activators of RasGRP when compared to PKCα with selectivities ranging from 6 to 65 fold. However, the parent compound 1 was appreciably more selective than any of the other isomers. In intact cells, modest differences in the patterns of translocation of the C1 domain targets were observed. Biophysical studies using giant vesicles as model membranes did show substantial differences in terms of molecular interactions impacting lipid organization, dynamics and membrane insertion. However, these differences did not yield correspondingly large changes in patterns of biological response, at least for the parameters examined. PMID:24794745

  1. Synthesis, Biological, and Biophysical Studies of DAG-indololactones Designed as Selective Activators of RasGRP

    PubMed Central

    Garcia, Lia C.; Donadío, Lucia Gandolfi; Mann, Ella; Kolusheva, Sofiya; Kedei, Noemi; Lewin, Nancy E.; Hill, Colin S.; Kelsey, Jessica S.; Yang, Jing; Esch, Timothy E.; Santos, Marina; Peach, Megan L.; Kelley, James A.; Blumberg, Peter M.; Jelinek, Raz; Marquez, Victor E.; Comin, Maria J.

    2014-01-01

    The development of selective agents capable of discriminating between protein kinase C (PKC) isoforms and other diacylglycerol (DAG)-responsive C1 domain-containing proteins represents an important challenge. Recent studies have highlighted the role that Ras guanine nucleotide-releasing protein (RasGRP) isoforms play both in immune responses as well as in the development of prostate cancer and melanoma, suggesting that the discovery of selective ligands could have potential therapeutic value. Thus far, the N-methyl-substituted indololactone 1 is the agonist with the highest reported potency and selectivity for RasGRP relative to PKC. Here we present the synthesis, binding studies, cellular assays and biophysical analysis of interactions with model membranes of a family of regioisomers of 1 (compounds 2 to 5) that differ in the position of the linkage between the indole ring and the lactone moiety. These structural variations were studied to explore the interaction of the active complex (C1 domain-ligand) with cellular membranes, which is believed to be an important factor for selectivity in the activation of DAG-responsive C1 domain containing signaling proteins. All compounds were potent and selective activators of RasGRP when compared to PKCα with selectivities ranging from 6 to 65 fold. However, the parent compound 1 was appreciably more selective than any of the other isomers. In intact cells, modest differences in the patterns of translocation of the C1 domain targets were observed. Biophysical studies using giant vesicles as model membranes did show substantial differences in terms of molecular interactions impacting lipid organization, dynamics and membrane insertion. However, these differences did not yield correspondingly large changes in patterns of biological response, at least for the parameters examined. PMID:24794745

  2. A channel simulator design study

    NASA Technical Reports Server (NTRS)

    Devito, D. M.; Goutmann, M. M.; Harper, R. C.

    1971-01-01

    A propagation path simulator was designed for the channel between a Tracking and Data Relay Satellite in geostationary orbit and a user spacecraft orbiting the earth at an altitude between 200 and 4000 kilometers. The simulator is required to duplicate the time varying parameters of the propagation channel.

  3. LSST: Cadence Design and Simulation

    NASA Astrophysics Data System (ADS)

    Cook, Kem H.; Pinto, P. A.; Delgado, F.; Miller, M.; Petry, C.; Saha, A.; Gee, P. A.; Tyson, J. A.; Ivezic, Z.; Jones, L.; LSST Collaboration

    2009-01-01

    The LSST Project has developed an operations simulator to investigate how best to observe the sky to achieve its multiple science goals. The simulator has a sophisticated model of the telescope and dome to properly constrain potential observing cadences. This model has also proven useful for investigating various engineering issues ranging from sizing of slew motors, to design of cryogen lines to the camera. The simulator is capable of balancing cadence goals from multiple science programs, and attempts to minimize time spent slewing as it carries out these goals. The operations simulator has been used to demonstrate a 'universal' cadence which delivers the science requirements for a deep cosmology survey, a Near Earth Object Survey and good sampling in the time domain. We will present the results of simulating 10 years of LSST operations using realistic seeing distributions, historical weather data, scheduled engineering downtime and current telescope and camera parameters. These simulations demonstrate the capability of the LSST to deliver a 25,000 square degree survey probing the time domain including 20,000 square degrees for a uniform deep, wide, fast survey, while effectively surveying for NEOs over the same area. We will also present our plans for future development of the simulator--better global minimization of slew time and eventual transition to a scheduler for the real LSST.

  4. The RAS Problem

    Cancer.gov

    More than 30% of all human cancers, including a high percentage of lung and colon cancers and 95% of pancreatic cancers are driven by mutations and possibly amplification (increased copies) of RAS genes.

  5. RAS Ordinary Meeting

    NASA Astrophysics Data System (ADS)

    2014-08-01

    Here are summarized talks from the February and March RAS Ordinary Meetings. The February meeting also enjoyed the Eddington Lecture from Prof. Lisa Kewley (Australian National University) on galaxy evolution in 3D.

  6. Spinning Rocket Simulator Turntable Design

    NASA Technical Reports Server (NTRS)

    Miles, Robert W.

    2001-01-01

    Contained herein is the research and data acquired from the Turntable Design portion of the Spinning Rocket Simulator (SRS) project. The SRS Project studies and eliminates the effect of coning on thrust-propelled spacecraft. This design and construction of the turntable adds a structural support for the SRS model and two degrees of freedom. The two degrees of freedom, radial and circumferential, will help develop a simulated thrust force perpendicular to the plane of the spacecraft model while undergoing an unstable coning motion. The Turntable consists of a ten-foot linear track mounted to a sprocket and press-fit to a thrust bearing. A two-inch high column grounded by a Triangular Baseplate supports this bearing and houses the slip rings and pressurized, air-line swivel. The thrust bearing allows the entire system to rotate under the moment applied through the chain-driven sprocket producing a circumferential degree of freedom. The radial degree of freedom is given to the model through the helically threaded linear track. This track allows the Model Support and Counter Balance to simultaneously reposition according to the coning motion of the Model. Two design factors that hinder the linear track are bending and twist due to torsion. A Standard Aluminum "C" channel significantly reduces these two deflections. Safety considerations dictate the design of all the components involved in this project.

  7. Simulation of a Wall-Bounded Flow using a Hybrid LES/RAS Approach with Turbulence Recycling

    NASA Technical Reports Server (NTRS)

    Quinlan, Jesse R.; Mcdaniel, James; Baurle, Robert A.

    2012-01-01

    Simulations of a supersonic recessed-cavity flow are performed using a hybrid large-eddy/ Reynolds-averaged simulation approach utilizing an inflow turbulence recycling procedure and hybridized inviscid flux scheme. Calorically perfect air enters the three-dimensional domain at a free stream Mach number of 2.92. Simulations are performed to assess grid sensitivity of the solution, efficacy of the turbulence recycling, and effect of the shock sensor used with the hybridized inviscid flux scheme. Analysis of the turbulent boundary layer upstream of the rearward-facing step for each case indicates excellent agreement with theoretical predictions. Mean velocity and pressure results are compared to Reynolds-averaged simulations and experimental data for each case, and these comparisons indicate good agreement on the finest grid. Simulations are repeated on a coarsened grid, and results indicate strong grid density sensitivity. The effect of turbulence recycling on the solution is illustrated by performing coarse grid simulations with and without inflow turbulence recycling. Two shock sensors, one of Ducros and one of Larsson, are assessed for use with the hybridized inviscid flux reconstruction scheme.

  8. Sensitivity of Cirrus and Mixed-phase Clouds to the Ice Nuclei Spectra in McRAS-AC: Single Column Model Simulations

    NASA Technical Reports Server (NTRS)

    Betancourt, R. Morales; Lee, D.; Oreopoulos, L.; Sud, Y. C.; Barahona, D.; Nenes, A.

    2012-01-01

    The salient features of mixed-phase and ice clouds in a GCM cloud scheme are examined using the ice formation parameterizations of Liu and Penner (LP) and Barahona and Nenes (BN). The performance of LP and BN ice nucleation parameterizations were assessed in the GEOS-5 AGCM using the McRAS-AC cloud microphysics framework in single column mode. Four dimensional assimilated data from the intensive observation period of ARM TWP-ICE campaign was used to drive the fluxes and lateral forcing. Simulation experiments where established to test the impact of each parameterization in the resulting cloud fields. Three commonly used IN spectra were utilized in the BN parameterization to described the availability of IN for heterogeneous ice nucleation. The results show large similarities in the cirrus cloud regime between all the schemes tested, in which ice crystal concentrations were within a factor of 10 regardless of the parameterization used. In mixed-phase clouds there are some persistent differences in cloud particle number concentration and size, as well as in cloud fraction, ice water mixing ratio, and ice water path. Contact freezing in the simulated mixed-phase clouds contributed to transfer liquid to ice efficiently, so that on average, the clouds were fully glaciated at T approximately 260K, irrespective of the ice nucleation parameterization used. Comparison of simulated ice water path to available satellite derived observations were also performed, finding that all the schemes tested with the BN parameterization predicted 20 average values of IWP within plus or minus 15% of the observations.

  9. Xyce parallel electronic simulator design.

    SciTech Connect

    Thornquist, Heidi K.; Rankin, Eric Lamont; Mei, Ting; Schiek, Richard Louis; Keiter, Eric Richard; Russo, Thomas V.

    2010-09-01

    This document is the Xyce Circuit Simulator developer guide. Xyce has been designed from the 'ground up' to be a SPICE-compatible, distributed memory parallel circuit simulator. While it is in many respects a research code, Xyce is intended to be a production simulator. As such, having software quality engineering (SQE) procedures in place to insure a high level of code quality and robustness are essential. Version control, issue tracking customer support, C++ style guildlines and the Xyce release process are all described. The Xyce Parallel Electronic Simulator has been under development at Sandia since 1999. Historically, Xyce has mostly been funded by ASC, the original focus of Xyce development has primarily been related to circuits for nuclear weapons. However, this has not been the only focus and it is expected that the project will diversify. Like many ASC projects, Xyce is a group development effort, which involves a number of researchers, engineers, scientists, mathmaticians and computer scientists. In addition to diversity of background, it is to be expected on long term projects for there to be a certain amount of staff turnover, as people move on to different projects. As a result, it is very important that the project maintain high software quality standards. The point of this document is to formally document a number of the software quality practices followed by the Xyce team in one place. Also, it is hoped that this document will be a good source of information for new developers.

  10. Fully conservative coupling of HEC-1 RAS with MODFLOW to simulate stream-aquifer interactions in a drainage basin 1960

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This work describes the application of a methodology designed to improve the representation of water surface profiles along open drain channels within the framework of regional groundwater modeling. The proposed methodology employs an iterative procedure that combines two public domain computational...

  11. RasGRP Ras guanine nucleotide exchange factors in cancer

    PubMed Central

    Ksionda, Olga; Limnander, Andre

    2014-01-01

    Summary RasGRP proteins are activators of Ras and other related small GTPases by the virtue of functioning as guanine nucleotide exchange factors (GEFs). In vertebrates, four RasGRP family members have been described. RasGRP-1 through −4 share many structural domains but there are also subtle differences between each of the different family members. Whereas SOS RasGEFs are ubiquitously expressed, RasGRP proteins are expressed in distinct patterns, such as in different cells of the hematopoietic system and in the brain. Most studies have concentrated on the role of RasGRP proteins in the development and function of immune cell types because of the predominant RasGRP expression profiles in these cells and the immune phenotypes of mice deficient for Rasgrp genes. However, more recent studies demonstrate that RasGRPs also play an important role in tumorigenesis. Examples are skin- and hematological-cancers but also solid malignancies such as melanoma or prostate cancer. These novel studies bring up many new and unanswered questions related to the molecular mechanism of RasGRP-driven oncogenesis, such as new receptor systems that RasGRP appears to respond to as well as regulatory mechanism for RasGRP expression that appear to be perturbed in these cancers. Here we will review some of the known aspects of RasGRP biology in lymphocytes and will discuss the exciting new notion that RasGRP Ras exchange factors play a role in oncogenesis downstream of various growth factor receptors. PMID:24744772

  12. Automated Simulation For Analysis And Design

    NASA Technical Reports Server (NTRS)

    Cantwell, E.; Shenk, Tim; Robinson, Peter; Upadhye, R.

    1992-01-01

    Design Assistant Workstation (DAWN) software being developed to facilitate simulation of qualitative and quantitative aspects of behavior of life-support system in spacecraft, chemical-processing plant, heating and cooling system of large building, or any of variety of systems including interacting process streams and processes. Used to analyze alternative design scenarios or specific designs of such systems. Expert system will automate part of design analysis: reason independently by simulating design scenarios and return to designer with overall evaluations and recommendations.

  13. Space shuttle visual simulation system design study

    NASA Technical Reports Server (NTRS)

    1973-01-01

    A recommendation and a specification for the visual simulation system design for the space shuttle mission simulator are presented. A recommended visual system is described which most nearly meets the visual design requirements. The cost analysis of the recommended system covering design, development, manufacturing, and installation is reported. Four alternate systems are analyzed.

  14. Engineering design and integration simulation utilization manual

    NASA Technical Reports Server (NTRS)

    Hirsch, G. N.

    1976-01-01

    A description of the Engineering Design Integration (EDIN) Simulation System as it exists at Johnson Space Center is provided. A discussion of the EDIN Simulation System capabilities and applications is presented.

  15. In service design by simulations

    SciTech Connect

    Nasr H. Ghoniem

    2004-03-14

    Irradiation of materials by energetic particles (e.g. electrons, ions and neutrons) is associated with very high internal power dissipation, which can drive the underlying nano- and microstructure far from normal equilibrium conditions. One of the most unusual responses in this connection is the ability of the material's nano- and microstructure to self-assemble in well-organized, two- and three-dimensional periodic arrangements. We reviewed and assessed experimental evidence and theoretical models pertaining to the physical understanding of nano- and microstructure self-organization under irradiation conditions. Experimental observations on the formation of self-organized defect clusters, dislocation loops, voids and bubbles were presented and critically assessed. Implantation of metals with energetic helium results in remarkable self-assembled bubble super-lattices with wavelengths (super-lattice parameters) in the range of 5-8 nm. Ion and neutron irradiation produce a wide variety of self-assembled 3-D defect walls and void lattices, with wavelengths that can be tailored in the range of 10's to 100's of nanometers. Theoretical models aimed at explaining these observations were introduced, and a consistent description of many features is outlined. The primary focus of the most recent modeling efforts, which are based on stability theory and concepts of non-linear dynamics, was to determine criteria for the evolution and spatial symmetry of self-organized microstructures. The correspondence between this theoretical framework and experimental observations was also examined, highlighting areas of agreement and pointing out unresolved questions. The main objective of this research was to develop new computational tools for in-service design and performance prediction of advanced fusion material systems by computational simulation. We also need to develop these computational tools to assist in planning and assessment of corresponding radiation experiments. In the

  16. Students Design a Depression Simulation.

    ERIC Educational Resources Information Center

    Roessler, Michael

    1987-01-01

    This article describes how an eighth grade class developed a computer-based social studies simulation on the Great Depression. Included are objectives for such development activities, a set of steps for guiding development, a discussion of potential difficulties and rewards, data on student reactions to simulation development, and information on…

  17. Converging Lens Simulation Design and Image Predictions

    ERIC Educational Resources Information Center

    Bryan, J. A.; Slough, S. W.

    2009-01-01

    While computer technology continues to enhance the teaching and learning of all science disciplines, computer simulations, in particular, have become exceptionally beneficial in physics education. In addition to the manner in which physics instructors integrate computer simulations into their instructional practices, the design of a simulation may…

  18. Shuttle mission simulator hardware conceptual design report

    NASA Technical Reports Server (NTRS)

    Burke, J. F.

    1973-01-01

    The detailed shuttle mission simulator hardware requirements are discussed. The conceptual design methods, or existing technology, whereby those requirements will be fulfilled are described. Information of a general nature on the total design problem plus specific details on how these requirements are to be satisfied are reported. The configuration of the simulator is described and the capabilities for various types of training are identified.

  19. Simulation and Spacecraft Design: Engineering Mars Landings.

    PubMed

    Conway, Erik M

    2015-10-01

    A key issue in history of technology that has received little attention is the use of simulation in engineering design. This article explores the use of both mechanical and numerical simulation in the design of the Mars atmospheric entry phases of the Viking and Mars Pathfinder missions to argue that engineers used both kinds of simulation to develop knowledge of their designs' likely behavior in the poorly known environment of Mars. Each kind of simulation could be used as a warrant of the other's fidelity, in an iterative process of knowledge construction. PMID:26593710

  20. [Design of an adjustable simulated lung].

    PubMed

    Xu, Liang; Luo, Zhe

    2011-03-01

    We designed an adjustable simulated lung for clinical use. Depending on the feature of adjustable resistance and compliance, the device could simulate various pathological changes of lung, such as obstructive diseases and restrictive diseases. Thru simulating various pathological conditions with the device, the clinicians could learn how to manipulate a mechanical ventilator. In addition, the device has a leakage equipment for simulating leakage of respiratory circuit, depending on which the clinicians could learn more about ventilators. PMID:21706793

  1. Simulator design for advanced ISDN satellite design and experiments

    NASA Technical Reports Server (NTRS)

    Pepin, Gerald R.

    1992-01-01

    This simulation design task completion report documents the simulation techniques associated with the network models of both the Interim Service ISDN (integrated services digital network) Satellite (ISIS) and the Full Service ISDN Satellite (FSIS) architectures. The ISIS network model design represents satellite systems like the Advanced Communication Technology Satellite (ACTS) orbiting switch. The FSIS architecture, the ultimate aim of this element of the Satellite Communications Applications Research (SCAR) program, moves all control and switching functions on-board the next generation ISDN communication satellite. The technical and operational parameters for the advanced ISDN communications satellite design will be obtained from the simulation of ISIS and FSIS engineering software models for their major subsystems. Discrete events simulation experiments will be performed with these models using various traffic scenarios, design parameters and operational procedures. The data from these simulations will be used to determine the engineering parameters for the advanced ISDN communications satellite.

  2. Simulation of integrated beam experiment designs

    SciTech Connect

    Grote, D.P.; Sharp, W.M.

    2004-06-11

    Simulation of designs of an Integrated Beam Experiment (IBX) class accelerator have been carried out. These simulations are an important tool for validating such designs. Issues such as envelope mismatch and emittance growth can be examined in a self-consistent manner, including the details of injection, accelerator transitions, long-term transport, and longitudinal compression. The simulations are three-dimensional and time-dependent, and begin at the source. They continue up through the end of the acceleration region, at which point the data is passed on to a separate simulation of the drift compression. Results are be presented.

  3. Prosthetic knee design by simulation

    SciTech Connect

    Hollerbach, K; Hollister, A

    1999-07-30

    Although 150,000 total knee replacement surgeries are performed annually in North America, current designs of knee prostheses have mechanical problems that include a limited range of motion, abnormal gait patterns, patellofemoral joint dysfunction, implant loosening or subsidence, and excessive wear. These problems fall into three categories: failure to reproduce normal joint kinematics, which results in altered limb function; bone-implant interface failure; and material failure. Modern computer technology can be used to design, prototype, and test new total knee implants. The design team uses the full range of CAD-CAM to design and produce implant prototypes for mechanical and clinical testing. Closer approximation of natural knee kinematics and kinetics is essential for improved patient function and diminished implant loads. Current knee replacement designs are based on 19th Century theories that the knee moves about a variable axis of rotation. Recent research has shown, however, that knee motion occurs about two fixed, offset axes of rotation. These aces are not perpendicular to the long axes of the bones or to each other, and the axes do not intersect. Bearing surfaces of mechanisms that move about axes of rotation are surfaces of revolution of those axes which advanced CAD technology can produce. Solids with surfaces of revolution for the two axes of rotation for the knee have been made using an HP9000 workstation and Structural Ideas Master Series CAD software at ArthroMotion. The implant's CAD model should closely replicate movements of the normal knee. The knee model will have a range of flexion-extension (FE) from -5 to 120 degrees. Movements include varus, valgus, internal and external rotation, as well as flexion and extension. The patellofemoral joint is aligned perpendicular to the FE axis and replicates the natural joint more closely than those of existing prostheses. The bearing surfaces will be more congruent than current designs and should

  4. Shuttle mission simulator software conceptual design

    NASA Technical Reports Server (NTRS)

    Burke, J. F.

    1973-01-01

    Software conceptual designs (SCD) are presented for meeting the simulator requirements for the shuttle missions. The major areas of the SCD discussed include: malfunction insertion, flight software, applications software, systems software, and computer complex.

  5. Refinery burner simulation design architecture summary.

    SciTech Connect

    Pollock, Guylaine M.; McDonald, Michael James; Halbgewachs, Ronald D.

    2011-10-01

    This report describes the architectural design for a high fidelity simulation of a refinery and refinery burner, including demonstrations of impacts to the refinery if errors occur during the refinery process. The refinery burner model and simulation are a part of the capabilities within the Sandia National Laboratories Virtual Control System Environment (VCSE). Three components comprise the simulation: HMIs developed with commercial SCADA software, a PLC controller, and visualization software. All of these components run on different machines. This design, documented after the simulation development, incorporates aspects not traditionally seen in an architectural design, but that were utilized in this particular demonstration development. Key to the success of this model development and presented in this report are the concepts of the multiple aspects of model design and development that must be considered to capture the necessary model representation fidelity of the physical systems.

  6. Simulation as an Aid to Experimental Design.

    ERIC Educational Resources Information Center

    Frazer, Jack W.; And Others

    1983-01-01

    Discusses simulation program to aid in the design of enzyme kinetic experimentation (includes sample runs). Concentration versus time profiles of any subset or all nine states of reactions can be displayed with/without simulated instrumental noise, allowing the user to estimate the practicality of any proposed experiment given known instrument…

  7. Simulation, Design Abstraction, and SystemC

    ERIC Educational Resources Information Center

    Harcourt, Ed

    2007-01-01

    SystemC is a system-level design and simulation language based on C++. We've been using SystemC for computer organization and design projects for the past several years. Because SystemC is embedded in C++ it contains the powerful abstraction mechanisms of C++ not found in traditional hardware description languages, such as support for…

  8. Computer Simulation For Design Of TWT's

    NASA Technical Reports Server (NTRS)

    Bartos, Karen F.; Fite, E. Brian; Shalkhauser, Kurt A.; Sharp, G. Richard

    1992-01-01

    A three-dimensional finite-element analytical technique facilitates design and fabrication of traveling-wave-tube (TWT) slow-wave structures. Used to perform thermal and mechanical analyses of TWT designed with variety of configurations, geometries, and materials. Using three-dimensional computer analysis, designer able to simulate building and testing of TWT, with consequent substantial saving of time and money. Technique enables detailed look into operation of traveling-wave tubes to help improve performance for future communications systems.

  9. Design and simulation of a gyroklystron amplifier

    SciTech Connect

    Chauhan, M. S. Swati, M. V.; Jain, P. K.

    2015-03-15

    In the present paper, a design methodology of the gyroklystron amplifier has been described and subsequently used for the design of a typically selected 200 kW, Ka-band, four-cavity gyroklystron amplifier. This conceptual device design has been validated through the 3D particle-in-cell (PIC) simulation and nonlinear analysis. Commercially available PIC simulation code “MAGIC” has been used for the electromagnetic study at the different location of the device RF interaction structure for the beam-absent case, i.e., eigenmode study as well as for the electron beam and RF wave interaction behaviour study in the beam present case of the gyroklystron. In addition, a practical problem of misalignment of the RF cavities with drift tubes within the tube has been also investigated and its effect on device performance studied. The analytical and simulation results confirmed the validity of the gyroklystron device design. The PIC simulation results of the present gyroklystron produced a stable RF output power of ∼218 kW for 0% velocity spread at 35 GHz, with ∼45 dB gain, 37% efficiency, and a bandwidth of 0.3% for a 70 kV, 8.2 A gyrating electron beam. The simulated values of RF output power have been found in agreement with the nonlinear analysis results within ∼5%. Further, the PIC simulation has been extended to study a practical problem of misalignment of the cavities axis and drift tube axis of the gyroklystron amplifier and found that the RF output power is more sensitive to misalignments in comparison to the device bandwidth. The present paper, gyroklystron device design, nonlinear analysis, and 3D PIC simulation using commercially available code had been systematically described would be of use to the high-power gyro-amplifier tube designers and research scientists.

  10. Design and simulation of a gyroklystron amplifier

    NASA Astrophysics Data System (ADS)

    Chauhan, M. S.; Swati, M. V.; Jain, P. K.

    2015-03-01

    In the present paper, a design methodology of the gyroklystron amplifier has been described and subsequently used for the design of a typically selected 200 kW, Ka-band, four-cavity gyroklystron amplifier. This conceptual device design has been validated through the 3D particle-in-cell (PIC) simulation and nonlinear analysis. Commercially available PIC simulation code "MAGIC" has been used for the electromagnetic study at the different location of the device RF interaction structure for the beam-absent case, i.e., eigenmode study as well as for the electron beam and RF wave interaction behaviour study in the beam present case of the gyroklystron. In addition, a practical problem of misalignment of the RF cavities with drift tubes within the tube has been also investigated and its effect on device performance studied. The analytical and simulation results confirmed the validity of the gyroklystron device design. The PIC simulation results of the present gyroklystron produced a stable RF output power of ˜218 kW for 0% velocity spread at 35 GHz, with ˜45 dB gain, 37% efficiency, and a bandwidth of 0.3% for a 70 kV, 8.2 A gyrating electron beam. The simulated values of RF output power have been found in agreement with the nonlinear analysis results within ˜5%. Further, the PIC simulation has been extended to study a practical problem of misalignment of the cavities axis and drift tube axis of the gyroklystron amplifier and found that the RF output power is more sensitive to misalignments in comparison to the device bandwidth. The present paper, gyroklystron device design, nonlinear analysis, and 3D PIC simulation using commercially available code had been systematically described would be of use to the high-power gyro-amplifier tube designers and research scientists.

  11. Detector simulation needs for detector designers

    SciTech Connect

    Hanson, G.G.

    1987-11-01

    Computer simulation of the components of SSC detectors and of the complete detectors will be very important for the designs of the detectors. The ratio of events from interesting physics to events from background processes is very low, so detailed understanding of detector response to the backgrounds is needed. Any large detector for the SSC will be very complex and expensive and every effort must be made to design detectors which will have excellent performance and will not have to undergo major rebuilding. Some areas in which computer simulation is particularly needed are pattern recognition in tracking detectors and development of shower simulation code which can be trusted as an aid in the design and optimization of calorimeters, including their electron identification performance. Existing codes require too much computer time to be practical and need to be compared with test beam data at energies of several hundred GeV. Computer simulation of the processing of the data, including electronics response to the signals from the detector components, processing of the data by microprocessors on the detector, the trigger, and data acquisition will be required. In this report we discuss the detector simulation needs for detector designers.

  12. Simulation as an aid to experimental design

    SciTech Connect

    Frazer, J.W.; Balaban, D.J.; Wang, J.L.

    1983-05-01

    A simulator of chemical reactions can aid the scientist in the design of experimentation. They are of great value when studying enzymatic kinetic reactions. One such simulator is a numerical ordinary differential equation solver which uses interactive graphics to provide the user with the capability to simulate an extremely wide range of enzyme reaction conditions for many types of single substrate reactions. The concentration vs. time profiles of any subset or all nine states of a complex reaction can be displayed with and without simulated instrumental noise. Thus the user can estimate the practicality of any proposed experimentation given known instrumental noise. The experimenter can readily determine which state provides the most information related to the proposed kinetic parameters and mechanism. A general discussion of the program including the nondimensionalization of the set of differential equations is included. Finally, several simulation examples are shown and the results discussed.

  13. Design of penicillin fermentation process simulation system

    NASA Astrophysics Data System (ADS)

    Qi, Xiaoyu; Yuan, Zhonghu; Qi, Xiaoxuan; Zhang, Wenqi

    2011-10-01

    Real-time monitoring for batch process attracts increasing attention. It can ensure safety and provide products with consistent quality. The design of simulation system of batch process fault diagnosis is of great significance. In this paper, penicillin fermentation, a typical non-linear, dynamic, multi-stage batch production process, is taken as the research object. A visual human-machine interactive simulation software system based on Windows operation system is developed. The simulation system can provide an effective platform for the research of batch process fault diagnosis.

  14. IAA RAS Radio Telescope Monitoring System

    NASA Astrophysics Data System (ADS)

    Mikhailov, A.; Lavrov, A.

    2007-07-01

    Institute of Applied Astronomy of the Russian Academy of Sciences (IAA RAS) has three identical radio telescopes, the receiving complex of which consists of five two-channel receivers of different bands, six cryogen systems, and additional devices: four local oscillators, phase calibration generators and IF commutator. The design, hardware and data communication protocol are described. The most convenient way to join the devices of the receiving complex into the common monitoring system is to use the interface which allows to connect numerous devices to the data bus. For the purpose of data communication regulation and to exclude conflicts, a data communication protocol has been designed, which operates with complex formatted data sequences. Formation of such sequences requires considerable data processing capability. That is provided by a microcontroller chip in each slave device. The test version of the software for the central computer has been developed in IAA RAS. We are developing the Mark IV FS software extension modules, which will allow us to control the receiving complex of the radio telescope by special SNAP commands from both operator input and schedule files. We are also developing procedures of automatic measurements of SEFD, system noise temperature and other parameters, available both in VLBI and single-dish modes of operation. The system described has been installed on all IAA RAS radio telescopes at "Svetloe", "Zelenchukskaya" and "Badary" observatories. It has proved to be working quite reliably and to show the perfonmance expected.

  15. Memory interface simulator: A computer design aid

    NASA Technical Reports Server (NTRS)

    Taylor, D. S.; Williams, T.; Weatherbee, J. E.

    1972-01-01

    Results are presented of a study conducted with a digital simulation model being used in the design of the Automatically Reconfigurable Modular Multiprocessor System (ARMMS), a candidate computer system for future manned and unmanned space missions. The model simulates the activity involved as instructions are fetched from random access memory for execution in one of the system central processing units. A series of model runs measured instruction execution time under various assumptions pertaining to the CPU's and the interface between the CPU's and RAM. Design tradeoffs are presented in the following areas: Bus widths, CPU microprogram read only memory cycle time, multiple instruction fetch, and instruction mix.

  16. [Role of RAS in prehypertension].

    PubMed

    Inaba, Shinji; Iwai, Masaru; Horiuchi, Masatsugu

    2008-08-01

    Hypertension has long been recognized as a major risk factor of several cardiovascular diseases. It is well known that the renin-angiotensin system(RAS) is involved in the pathogenesis of both hypertension and hypertensive end-organ damage. Untreated hypertension is self-accelerating condition through RAS stimulation. Activation of RAS contributes to the transition from borderline hypertension to established hypertension. Recently, "the Seventh Report of Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7)" proposed a new classification of borderline blood pressure levels, as "prehypertension". The therapeutic focus has begun to shift from the therapy of established hypertension to the prevention of hypertension. This review addressed the relationship between hypertension, prehypertension and the role of RAS. PMID:18700549

  17. [Vernier Anode Design and Image Simulation].

    PubMed

    Zhao, Ai-rong; Ni, Qi-liang; Song, Ke-fei

    2015-12-01

    Based-MCP position-sensitive anode photon-counting imaging detector is good at detecting extremely faint light, which includes micro-channel plate (MCP), position-sensitive anode and readout, and the performances of these detectors are mainly decided by the position-sensitive anode. As a charge division anode, Vernier anode using cyclically varying electrode areas which replaces the linearly varying electrodes of wedge-strip anode can get better resolution and greater electrode dynamic range. Simulation and design of the Vernier anode based on Vernier's decode principle are given here. Firstly, we introduce the decode and design principle of Vernier anode with nine electrodes in vector way, and get the design parameters which are the pitch, amplitude and the coarse wavelength of electrode. Secondly, we analyze the effect of every design parameters to the imaging of the detector. We simulate the electron cloud, the Vernier anode and the detector imaging using Labview software and get the relationship between the pitch and the coarse wavelength of the anode. Simultaneously, we get the corresponding electron cloud for the designing parameters. Based on the result of the simulation and the practical machining demand, a nine electrodes Vernier anode was designed and fabricated which has a pitch of 891 µm, insulation width of 25 µm, amplitude of 50 µm, coarse pixel numbers of 5. PMID:26964205

  18. The Process Design Courses at Pennsylvania: Impact of Process Simulators.

    ERIC Educational Resources Information Center

    Seider, Warren D.

    1984-01-01

    Describes the use and impact of process design simulators in process design courses. Discusses topics covered, texts used, computer design simulations, and how they are integrated into the process survey course as well as in plant design projects. (JM)

  19. Designing Online Scaffolds for Interactive Computer Simulation

    ERIC Educational Resources Information Center

    Chen, Ching-Huei; Wu, I-Chia; Jen, Fen-Lan

    2013-01-01

    The purpose of this study was to examine the effectiveness of online scaffolds in computer simulation to facilitate students' science learning. We first introduced online scaffolds to assist and model students' science learning and to demonstrate how a system embedded with online scaffolds can be designed and implemented to help high…

  20. Thin-film designs by simulated annealing

    NASA Astrophysics Data System (ADS)

    Boudet, T.; Chaton, P.; Herault, L.; Gonon, G.; Jouanet, L.; Keller, P.

    1996-11-01

    With the increasing power of computers, new methods in synthesis of optical multilayer systems have appeared. Among these, the simulated-annealing algorithm has proved its efficiency in several fields of physics. We propose to show its performances in the field of optical multilayer systems through different filter designs.

  1. Dynamic Process Simulation for Analysis and Design.

    ERIC Educational Resources Information Center

    Nuttall, Herbert E., Jr.; Himmelblau, David M.

    A computer program for the simulation of complex continuous process in real-time in an interactive mode is described. The program is user oriented, flexible, and provides both numerical and graphic output. The program has been used in classroom teaching and computer aided design. Typical input and output are illustrated for a sample problem to…

  2. Design and Simulation of Hybridization Experiments

    Energy Science and Technology Software Center (ESTSC)

    1995-11-28

    DB EXP DESIGN is a suite of three UNIX shell-like programs, DWC which computes oligomer composition of DNA texts using directed acyclic word data structures; DWO, which simulates hybridization experiments; and DMI, which calculates the information contenet of individual probes, their mutual information content, and their joint information content through estimation of Markov trees.

  3. Symbolic computation in system simulation and design

    NASA Astrophysics Data System (ADS)

    Evans, Brian L.; Gu, Steve X.; Kalavade, Asa; Lee, Edward A.

    1995-06-01

    This paper examines some of the roles that symbolic computation plays in assisting system- level simulation and design. By symbolic computation, we mean programs like Mathematica that perform symbolic algebra and apply transformation rules based on algebraic identities. At a behavioral level, symbolic computation can compute parameters, generate new models, and optimize parameter settings. At the synthesis level, symbolic computation can work in tandem with synthesis tools to rewrite cascade and parallel combinations on components in sub- systems to meet design constraints. Symbolic computation represents one type of tool that may be invoked in the complex flow of the system design process. The paper discusses the qualities that a formal infrastructure for managing system design should have. The paper also describes an implementation of this infrastructure called DesignMaker, implemented in the Ptolemy environment, which manages the flow of tool invocations in an efficient manner using a graphical file dependency mechanism.

  4. ALT-3 target design and simulations

    SciTech Connect

    Peterson, Jeffrey H

    2011-01-12

    ALT-3 is an experiment being designed in collaboration between Russian VNIIEF scientists and LANL that aims to conduct high velocity material experiments to measure shock velocities and pressures near 1 TPa. The DEMG (Disck Explosive Magnetic Generator) is used to drive> 60MA currents to accelerate an aluminum liner to speeds in excess of 20 km/s. 1-D and 2-D simulations of the aluminum target are presented with information on the free surface velocity profile, the state of the target, and the shock velocity in the target. 2-D simulations are presented showing the different targets available as well as a scenario with a perturbed liner impacter.

  5. Design and simulation of MEMS capacitive magnetometer

    NASA Astrophysics Data System (ADS)

    Jyoti, Aditi, Tripathi, C. C.; Gopal, Ram

    2016-04-01

    This paper presents the design and simulation of a MEMS Capacitive Magnetometer using FEM (Finite Element Method) tool COMSOL Multiphysics 4.3b and results from this simulation are closely matched with analytically calculated results. A comb drive structure is used for actuation purpose which operates at resonant frequency of device is 11.791 kHz to achieve maximum displacement. A magnetic field in z-axis can be detected by this comb drive structure. Quality factor of MEMS capacitive magnetometer obtained is 18 and it has good linear response in the magnetic field range of 100 µT.

  6. Parachute system design, analysis, and simulation tool

    SciTech Connect

    Sundberg, W.D.; McBride, D.D.; Gwinn, K.W.; Waye, D.E.; Hailey, C.E.

    1992-01-01

    For over twenty years designers at Sandia National Laboratories have developed various parachute simulation codes to model deployment, inflation, loading, trajectories, aircraft downwash and line sail. In addition to these codes, material property data bases have been acquired. Recently we have initiated project to integrate these codes and data bases into a single software tool entitled SPARSYS (Sandia PARachute SYstem Simulation). We have constructed a graphical user interface as the driver and framework for SPARSYS. In this paper we present a status report on SPARSYS describing progress in developing and incorporating independent modules, in developing an integrated trajectory package, and in developing a materials data base including high-rate-of-strain data.

  7. Comparative proteomic analysis of compartmentalised Ras signalling

    PubMed Central

    Hernandez-Valladares, Maria; Prior, Ian A.

    2015-01-01

    Ras proteins are membrane bound signalling hubs that operate from both the cell surface and endomembrane compartments. However, the extent to which intracellular pools of Ras can contribute to cell signalling is debated. To address this, we have performed a global screen of compartmentalised Ras signalling. We find that whilst ER/Golgi- and endosomal-Ras only generate weak outputs, Ras localised to the mitochondria or Golgi significantly and distinctly influence both the abundance and phosphorylation of a wide range of proteins analysed. Our data reveal that ~80% of phosphosites exhibiting large (≥1.5-fold) changes compared to control can be modulated by organellar Ras signalling. The majority of compartmentalised Ras-specific responses are predicted to influence gene expression, RNA splicing and cell proliferation. Our analysis reinforces the concept that compartmentalisation influences Ras signalling and provides detailed insight into the widespread modulation of responses downstream of endomembranous Ras signalling. PMID:26620772

  8. Orbit Design and Simulation for Kufasat Nanosatellite

    NASA Astrophysics Data System (ADS)

    Mahdi, Mohammed Chessab

    2015-12-01

    Orbit design for KufaSat Nano-satellites is presented. Polar orbit is selected for the KufaSat mission. The orbit was designed with an Inclination which enables the satellite to see every part of the earth. KufaSat has a payload for imaging purposes which require a large amount of power, so the orbit is determined to be sun synchronous in order to provide the power through solar panels. The KufaSat mission is designed for the low earth orbit. The six initial Keplerian Elements of KufaSat are calculated. The orbit design of KufaSat according to the calculated Keplerian elements has been simulated and analyzed by using MATLAB first and then by using General Mission Analysis Tool.

  9. Cardiac remodelling and RAS inhibition.

    PubMed

    Ferrario, Carlos M

    2016-06-01

    Risk factors such as hypertension and diabetes are known to augment the activity and tissue expression of angiotensin II (Ang II), the major effector peptide of the renin-angiotensin system (RAS). Overstimulation of the RAS has been implicated in a chain of events that contribute to the pathogenesis of cardiovascular (CV) disease, including the development of cardiac remodelling. This chain of events has been termed the CV continuum. The concept of CV disease existing as a continuum was first proposed in 1991 and it is believed that intervention at any point within the continuum can modify disease progression. Treatment with antihypertensive agents may result in regression of left ventricular hypertrophy, with different drug classes exhibiting different degrees of efficacy. The greatest decrease in left ventricular mass is observed following treatment with angiotensin converting enzyme inhibitors (ACE-Is), which inhibit Ang II formation. Although ACE-Is and angiotensin receptor blockers (ARBs) provide significant benefits in terms of CV events and stroke, mortality remains high. This is partly due to a failure to completely suppress the RAS, and, as our knowledge has increased, an escape phenomenon has been proposed whereby the human sequence of the 12 amino acid substrate angiotensin-(1-12) is converted to Ang II by the mast cell protease, chymase. Angiotensin-(1-12) is abundant in a wide range of organs and has been shown to increase blood pressure in animal models, an effect abolished by the presence of ACE-Is or ARBs. This review explores the CV continuum, in addition to examining the influence of the RAS. We also consider novel pathways within the RAS and how new therapeutic approaches that target this are required to further reduce Ang II formation, and so provide patients with additional benefits from a more complete blockade of the RAS. PMID:27105891

  10. Design and simulation of a neutron facility.

    PubMed

    Studenski, Matthew T; Kearfott, Kimberlee J

    2007-02-01

    State and other regulatory entities require that for any facility housing a particle accelerator the surrounding areas must be restricted to public access unless the dose equivalent rate is less than 0.02 mSv h at 5 cm from any accessible wall surrounding the facility under conditions of maximum radiation output. A Monte Carlo radiation transport simulation code, MCNP5, was used to design a proposed facility to shield two D-T neutron generators and one D-D neutron generator. A number of different designs were simulated, but due to cost and space issues a small concrete cave proved to be the best solution for the shielding problem. With this design, all of the neutron generators could be used and all of the rooms surrounding the neutron facility could be considered unrestricted to public access. To prevent unauthorized access into the restricted area of the neutron facility, light curtains, warning lights, door interlocks, and rope barriers will be built into the facility. PMID:17228186

  11. Digital autopilots: Design considerations and simulator evaluations

    NASA Technical Reports Server (NTRS)

    Osder, S.; Neuman, F.; Foster, J.

    1971-01-01

    The development of a digital autopilot program for a transport aircraft and the evaluation of that system's performance on a transport aircraft simulator is discussed. The digital autopilot includes three axis attitude stabilization, automatic throttle control and flight path guidance functions with emphasis on the mode progression from descent into the terminal area through automatic landing. The study effort involved a sequence of tasks starting with the definition of detailed system block diagrams of control laws followed by a flow charting and programming phase and concluding with performance verification using the transport aircraft simulation. The autopilot control laws were programmed in FORTRAN 4 in order to isolate the design process from requirements peculiar to an individual computer.

  12. Simulated Data for High Temperature Composite Design

    NASA Technical Reports Server (NTRS)

    Chamis, Christos C.; Abumeri, Galib H.

    2006-01-01

    The paper describes an effective formal method that can be used to simulate design properties for composites that is inclusive of all the effects that influence those properties. This effective simulation method is integrated computer codes that include composite micromechanics, composite macromechanics, laminate theory, structural analysis, and multi-factor interaction model. Demonstration of the method includes sample examples for static, thermal, and fracture reliability for a unidirectional metal matrix composite as well as rupture strength and fatigue strength for a high temperature super alloy. Typical results obtained for a unidirectional composite show that the thermal properties are more sensitive to internal local damage, the longitudinal properties degrade slowly with temperature, the transverse and shear properties degrade rapidly with temperature as do rupture strength and fatigue strength for super alloys.

  13. Therapeutic Strategies for Targeting Ras Proteins

    PubMed Central

    Gysin, Stephan; Salt, Megan; Young, Amy; McCormick, Frank

    2011-01-01

    Ras genes are frequently activated in cancer. Attempts to develop drugs that target mutant Ras proteins have, so far, been unsuccessful. Tumors bearing these mutations, therefore, remain among the most difficult to treat. Most efforts to block activated Ras have focused on pathways downstream. Drugs that inhibit Raf kinase have shown clinical benefit in the treatment of malignant melanoma. However, these drugs have failed to show clinical benefit in Ras mutant tumors. It remains unclear to what extent Ras depends on Raf kinase for transforming activity, even though Raf proteins bind directly to Ras and are certainly major effectors of Ras action in normal cells and in development. Furthermore, Raf kinase inhibitors can lead to paradoxical activation of the MAPK pathway. MEK inhibitors block the Ras-MAPK pathway, but often activate the PI3’-kinase, and have shown little clinical benefit as single agents. This activation is mediated by EGF-R and other receptor tyrosine kinases through relief of a negative feedback loop from ERK. Drug combinations that target multiple points within the Ras signaling network are likely to be necessary to achieve substantial clinical benefit. Other effectors may also contribute to Ras signaling and provide a source of targets. In addition, unbiased screens for genes necessary for Ras transformation have revealed new potential targets and have added to our understanding of Ras cancer biology. PMID:21779505

  14. VOCs monitoring system simulation and design

    NASA Astrophysics Data System (ADS)

    Caldararu, Florin; Vasile, Alexandru; Vatra, Cosmin

    2010-11-01

    The designed and simulated system will be used in the tanning industry, for Volatile Organic Compound (VOC) measurements. In this industry, about 90% of the solvent contained in the emulsions evaporates during its application, giving rise to VOC, which are at the same time hazardous atmospheric pollutants and one of the sources of ground level photochemical ozone formation. It results that a monitoring system is necessary in a leather finishing process, in order to detect hazardous VOC concentration and conducting process in order of VOC concentration diminishing. The paper presents the design of a VOC monitoring system, which includes sensors for VOCs and temperature, the conditioning circuitry for these sensors, the suction system of the gas in the hood, the data acquisition and the computing system and graphic interface. The used sensor in the detection system is a semiconductor sensor, produced by Figaro Engineering Inc., characterized by a short response time, high sensitivity at almost all VOC substances. The design of the conditioning circuitry and data acquisition is done in order to compensate the sensor response variation with temperature and to maintain the low response time of the sensor. The temperature compensation is obtained by using a thermistor circuitry, and the compensation is done within the software design. A Mitsubishi PLC is used to receive the output signals of the circuits including the sensor and of the thermistor, respectively. The acquisition and computing system is done using Mitsubishi ALPHA 2 controller and a graphical terminal, GOT 1000.

  15. Simulation-based disassembly systems design

    NASA Astrophysics Data System (ADS)

    Ohlendorf, Martin; Herrmann, Christoph; Hesselbach, Juergen

    2004-02-01

    Recycling of Waste of Electrical and Electronic Equipment (WEEE) is a matter of actual concern, driven by economic, ecological and legislative reasons. Here, disassembly as the first step of the treatment process plays a key role. To achieve sustainable progress in WEEE disassembly, the key is not to limit analysis and planning to merely disassembly processes in a narrow sense, but to consider entire disassembly plants including additional aspects such as internal logistics, storage, sorting etc. as well. In this regard, the paper presents ways of designing, dimensioning, structuring and modeling different disassembly systems. Goal is to achieve efficient and economic disassembly systems that allow recycling processes complying with legal requirements. Moreover, advantages of applying simulation software tools that are widespread and successfully utilized in conventional industry sectors are addressed. They support systematic disassembly planning by means of simulation experiments including consecutive efficiency evaluation. Consequently, anticipatory recycling planning considering various scenarios is enabled and decisions about which types of disassembly systems evidence appropriateness for specific circumstances such as product spectrum, throughput, disassembly depth etc. is supported. Furthermore, integration of simulation based disassembly planning in a holistic concept with configuration of interfaces and data utilization including cost aspects is described.

  16. Ras in Cancer and Developmental Diseases

    PubMed Central

    Fernández-Medarde, Alberto; Santos, Eugenio

    2011-01-01

    Somatic, gain-of-function mutations in ras genes were the first specific genetic alterations identified in human cancer about 3 decades ago. Studies during the last quarter century have characterized the Ras proteins as essential components of signaling networks controlling cellular proliferation, differentiation, or survival. The oncogenic mutations of the H-ras, N-ras, or K-ras genes frequently found in human tumors are known to throw off balance the normal outcome of those signaling pathways, thus leading to tumor development. Oncogenic mutations in a number of other upstream or downstream components of Ras signaling pathways (including membrane RTKs or cytosolic kinases) have been detected more recently in association with a variety of cancers. Interestingly, the oncogenic Ras mutations and the mutations in other components of Ras/MAPK signaling pathways appear to be mutually exclusive events in most tumors, indicating that deregulation of Ras-dependent signaling is the essential requirement for tumorigenesis. In contrast to sporadic tumors, separate studies have identified germline mutations in Ras and various other components of Ras signaling pathways that occur in specific association with a number of different familial, developmental syndromes frequently sharing common phenotypic cardiofaciocutaneous features. Finally, even without being a causative force, defective Ras signaling has been cited as a contributing factor to many other human illnesses, including diabetes and immunological and inflammatory disorders. We aim this review at summarizing and updating current knowledge on the contribution of Ras mutations and altered Ras signaling to development of various tumoral and nontumoral pathologies. PMID:21779504

  17. Design and simulation of e-calendar system circuits

    NASA Astrophysics Data System (ADS)

    Liu, Li-jun

    2015-02-01

    The digital calendar circuits controlled by 80C52 have been designed based on Proteus simulation software. The whole design process is made of three parts: hardware circuits, software programming and software simulation. Finally, it shows that the circuit design of hardware and software is correct through Proteus software simulation. The method of circuit design is systematic and practical, which will provide certain design ideas and reference value for display circuit in the future.

  18. Lead identification for the K-Ras protein: virtual screening and combinatorial fragment-based approaches

    PubMed Central

    Pathan, Akbar Ali Khan; Panthi, Bhavana; Khan, Zahid; Koppula, Purushotham Reddy; Alanazi, Mohammed Saud; Sachchidanand; Parine, Narasimha Reddy; Chourasia, Mukesh

    2016-01-01

    Objective Kirsten rat sarcoma (K-Ras) protein is a member of Ras family belonging to the small guanosine triphosphatases superfamily. The members of this family share a conserved structure and biochemical properties, acting as binary molecular switches. The guanosine triphosphate-bound active K-Ras interacts with a range of effectors, resulting in the stimulation of downstream signaling pathways regulating cell proliferation, differentiation, and apoptosis. Efforts to target K-Ras have been unsuccessful until now, placing it among high-value molecules against which developing a therapy would have an enormous impact. K-Ras transduces signals when it binds to guanosine triphosphate by directly binding to downstream effector proteins, but in case of guanosine diphosphate-bound conformation, these interactions get disrupted. Methods In the present study, we targeted the nucleotide-binding site in the “on” and “off” state conformations of the K-Ras protein to find out suitable lead compounds. A structure-based virtual screening approach has been used to screen compounds from different databases, followed by a combinatorial fragment-based approach to design the apposite lead for the K-Ras protein. Results Interestingly, the designed compounds exhibit a binding preference for the “off” state over “on” state conformation of K-Ras protein. Moreover, the designed compounds’ interactions are similar to guanosine diphosphate and, thus, could presumably act as a potential lead for K-Ras. The predicted drug-likeness properties of these compounds suggest that these compounds follow the Lipinski’s rule of five and have tolerable absorption, distribution, metabolism, excretion and toxicity values. Conclusion Thus, through the current study, we propose targeting only “off” state conformations as a promising strategy for the design of reversible inhibitors to pharmacologically inhibit distinct conformations of K-Ras protein. PMID:27217775

  19. Muon RLA - design status and simulations

    NASA Astrophysics Data System (ADS)

    Beard, K. B.; Bogacz, S. A.; Morozov, V. S.; Roblin, Y. R.

    2013-02-01

    The Neutrino Factory baseline design involves a complex chain of accelerators beginning with a linac. This first pre-linac follows the capture and bunching section and accelerates the muons from about 244 to 900 MeV and must accept a high emittance beam about 30 cm wide with a 10% energy spread. It uses counterwound, shielded superconducting solenoids and 201 MHz superconducting cavities, and currently consists of 24 3 m and 24 5 m long cryomodules. The next stage is a 1st dogbone-shaped RLA that takes the total energy from 900 MeV to 3.6 GeV in 4.5 passes, followed by a 2nd RLA that takes the energy from 3.6 to 12.6 GeV in 4.5 passes. Simulations are in progress to optimize the optics and determine the radiation loads from beam loss and muon decay.

  20. Innovations in infrared scene simulator design

    NASA Astrophysics Data System (ADS)

    Lane, Richard; Heath, Jeffery L.

    1998-07-01

    The MIRAGE (Multispectral Infrared Animation Generation Equipment) Dynamic Infrared Scene Projector, is a joint project developed by Santa Barbara Infrared, Inc. and Indigo Systems Corporation. MIRAGE is a complete infrared scene projector, accepting 3-D rendered analog or digital scene data at its input, and providing all other electronics, collimated optics, calibration and thermal support subsystems needed to simulated a unit under test with high-fidelity, dynamic infrared scenes. At the heart of MIRAGE is a 512 X 512 emitter array, with key innovations that solve several problems of existing designs. The read-in integrated circuit (RIIC) features 'snapshot' updating of the entire 512 X 512 resistive array, thus solving synchronization and latency problems inherent in 'rolling- update' type designs, where data is always changing somewhere on the emitter array at any given time. This custom mixed- signal RIIC also accepts digital scene information at its input, and uses on-board D/A converters and individual unit- cell buffer amplifiers to create analog scene levels, eliminating the complexity, noise, and limitations of speed and dynamic range associated with external generation of analog scene levels. The proprietary process used to create the advanced technology micro-membrane emitter elements allows a wide choice of resistor and structure materials while preserving the dissipation and providing a thermal time constant of the order of 5 ms. These innovations, along with a compact electronics subsystem based on a standard desktop PC, greatly reduce the complexity of the required external support electronics, resulting in a smaller, higher performance dynamic scene simulator system.

  1. How to Target Activated Ras Proteins: Direct Inhibition vs. Induced Mislocalization.

    PubMed

    Brock, Ethan J; Ji, Kyungmin; Reiners, John J; Mattingly, Raymond R

    2016-01-01

    Oncogenic Ras proteins are a driving force in a significant set of human cancers and wildtype, unmutated Ras proteins likely contribute to the malignant phenotype of many more. The overall challenge of targeting activated Ras proteins has great promise to treat cancer, but this goal has yet to be achieved. Significant efforts and resources have been committed to inhibiting Ras, but these energies have so far made little impact in the clinic. Direct attempts to target activated Ras proteins have faced many obstacles, including the fundamental nature of the gain-of-function oncogenic activity being produced by a loss-of-function at the biochemical level. Nevertheless, there has been very promising recent pre-clinical progress. The major strategy that has so far reached the clinic aimed to inhibit activated Ras indirectly through blocking its post-translational modification and inducing its mislocalization. While these efforts to indirectly target Ras through inhibition of farnesyl transferase (FTase) were rationally designed, this strategy suffered from insufficient attention to the distinctions between the isoforms of Ras. This led to subsequent failures in large-scale clinical trials targeting K-Ras driven lung, colon, and pancreatic cancers. Despite these setbacks, efforts to indirectly target activated Ras through inducing its mislocalization have persisted. It is plausible that FTase inhibitors may still have some utility in the clinic, perhaps in combination with statins or other agents. Alternative approaches for inducing mislocalization of Ras through disruption of its palmitoylation cycle or interaction with chaperone proteins are in early stages of development. PMID:26423696

  2. Modeling the Transcriptional Consequences of Epidermal Growth Factor Receptor Ablation in Ras-Initiated Squamous Cancer

    PubMed Central

    Wright, Lisa Nolan; Ryscavage, Andrew; Merlino, Glenn; Yuspa, Stuart H.

    2011-01-01

    Purpose EGFR targeted therapy is in clinical use to treat squamous cell carcinoma of the head and neck and other cancers of lining epithelium. Ras mutations in these tumors are a negative prognostic factor for response and skin inflammation is an adverse reaction to therapy. We investigated transcriptional and biochemical changes that could account for the confounding effects of RAS activation and inflammation in a squamous tissue. Experimental Design We performed gene expression profiling on oncogenic Ras transformed and wildtype mouse and human keratinocytes with EGFR ablated chronically by genetic deletion or acutely by drug treatment and followed leads provided by pathway analysis with biochemical studies. Results We identified a 25 gene signature specific to the Ras-EGFR ablation interaction and a distinct 19 gene EGFR ablation signature on normal keratinocytes. EGFR ablation in the context of wildtype Ras reduces ontologies favoring cell cycle control and transcription while oncogenic Ras enriches ontologies for ion channels and membrane transporters, particularly focused on calcium homeostasis. Ontologies between chronic EGFR ablation and acute pharmacological ablation were unique, both with and without Ras activation. p38α is activated in response to abrogation of EGFR signaling under conditions of Ras activation in both mouse and human keratinocytes and in RAS transformed tumor orthografts of EGFR ablated mouse keratinocytes. EGFR ablation in the absence of oncogenic Ras revealed Erk and IL-1β related pathways. Conclusion These findings reveal unrecognized interactions between Ras and EGFR signaling in squamous tumor cells that could influence the therapeutic response to EGFR ablation therapy. PMID:22068661

  3. Constructivist Design of Graphic Computer Simulations.

    ERIC Educational Resources Information Center

    Black, John B.; And Others

    Two graphic computer simulations have been prepared for teaching high school and middle school students about how business organizations and financial systems work: "Parkside," which simulates managing a hotel; and "Guestwear," which simulates managing a clothing manufacturer. Both simulations are based on six principles of constructivist design…

  4. Inhibition of malignant thyroid carcinoma cell proliferation by Ras and galectin-3 inhibitors

    PubMed Central

    Menachem, A; Bodner, O; Pastor, J; Raz, A; Kloog, Y

    2015-01-01

    Anaplastic Thyroid carcinoma is an extremely aggressive solid tumor that resists most treatments and is almost always fatal. Galectin-3 (Gal-3) is an important marker for thyroid carcinomas and a scaffold of the K-Ras protein. S-trans, transfarnesylthiosalicylic acid (FTS; Salirasib) is a Ras inhibitor that inhibits the active forms of Ras proteins. Modified citrus pectin (MCP) is a water-soluble citrus-fruit-derived polysaccharide fiber that specifically inhibits Gal-3. The aim of this study was to develop a novel drug combination designed to treat aggressive anaplastic thyroid carcinoma. Combined treatment with FTS and MCP inhibited anaplastic thyroid cells proliferation in vitro by inducing cell cycle arrest and increasing apoptosis rate. Immunoblot analysis revealed a significant decrease in Pan-Ras, K-Ras, Ras-GTP, p-ERK, p53, and Gal-3 expression levels and significant increase in p21 expression levels. In nude mice, treatment with FTS and MCP inhibited tumor growth. Levels of Gal-3, K-Ras-GTP, and p-ERK were significantly decreased. To conclude, our results suggest K-Ras and Gal-3 as potential targets in anaplastic thyroid tumors and herald a novel treatment for highly aggressive anaplastic thyroid carcinoma. PMID:27551476

  5. A computer simulator for development of engineering system design methodologies

    NASA Technical Reports Server (NTRS)

    Padula, S. L.; Sobieszczanski-Sobieski, J.

    1987-01-01

    A computer program designed to simulate and improve engineering system design methodology is described. The simulator mimics the qualitative behavior and data couplings occurring among the subsystems of a complex engineering system. It eliminates the engineering analyses in the subsystems by replacing them with judiciously chosen analytical functions. With the cost of analysis eliminated, the simulator is used for experimentation with a large variety of candidate algorithms for multilevel design optimization to choose the best ones for the actual application. Thus, the simulator serves as a development tool for multilevel design optimization strategy. The simulator concept, implementation, and status are described and illustrated with examples.

  6. Targeting oncogenic Ras signaling in hematologic malignancies

    PubMed Central

    Ward, Ashley F.; Braun, Benjamin S.

    2012-01-01

    Ras proteins are critical nodes in cellular signaling that integrate inputs from activated cell surface receptors and other stimuli to modulate cell fate through a complex network of effector pathways. Oncogenic RAS mutations are found in ∼ 25% of human cancers and are highly prevalent in hematopoietic malignancies. Because of their structural and biochemical properties, oncogenic Ras proteins are exceedingly difficult targets for rational drug discovery, and no mechanism-based therapies exist for cancers with RAS mutations. This article reviews the properties of normal and oncogenic Ras proteins, the prevalence and likely pathogenic role of NRAS, KRAS, and NF1 mutations in hematopoietic malignancies, relevant animal models of these cancers, and implications for drug discovery. Because hematologic malignancies are experimentally tractable, they are especially valuable platforms for addressing the fundamental question of how to reverse the adverse biochemical output of oncogenic Ras in cancer. PMID:22898602

  7. Optical design of MAORY turbulence simulator

    NASA Astrophysics Data System (ADS)

    Lombini, Matteo; Diolaiti, Emiliano; Arcidiacono, Carmelo; Bregoli, Giovanni; Cosentino, Giuseppe; De Rosa, Adriano; Foppiani, Italo; Schreiber, Laura

    2013-12-01

    MAORY, the foreseen multi conjugate adaptive optics module for the Extremely Large Telescope, has the goal to relay the telescope focal plane achieving a high and uniform correction of the atmosphere induced wavefront aberrations, over a 2 arcmin field of view in a large fraction of the sky. The aberrated wavefronts will be measured by 6 Sodium laser guide stars, arranged symmetrically over a 2 arcmin circular field of view, and by 3 natural guide stars in a searching field of view up to 2.6 arcmin and will be corrected by means of the telescope embedded adaptive mirror M4 and two post focal deformable mirrors. At the end of the integration phase performance tests of MAORY adaptive correction capability must be carried out. We present in this paper the optical design of a turbulence generator that will feed the MAORY entrance focal plane with sources representing laser and natural guide stars with realistic time varying aberrated wavefronts. The focal plane diameter (~500 mm) and the distance between the natural and the laser guide star focal plane positions (4-6 m) discourage a monolithic design of the turbulence generator. Our approach consists in separating the optical paths of the different sources in order to use smaller and thus more feasible components. The time varying atmospheric turbulence at several altitudes over the telescope is planned to be carried out placing before the pupil stop few phase screens on moving stages. Set of mirrors focus both the natural and laser stars at the expected positions of the real sources, preserving the telescope optical parameters as the exit pupil position, focal ratio, field curvature. Three laser guide stars and seven natural guide stars, one on axis and 6 at 1 arcmin off-axis, can be simulated with diffraction limit size.

  8. RAS and Hedgehog--partners in crime.

    PubMed

    Lauth, Matthias

    2011-01-01

    Both RAS and Hedgehog (HH) pathway activation can be found in approximately one third of all cancers. In many cases, this activation occurs in the same tumor types, suggesting a positive impact of a simultaneous activation of RAS and HH on tumor development. This review aims to summarize the current knowledge about the molecular and functional crosstalk of RAS and HH signaling in the development of hyperproliferative disease. PMID:21622175

  9. RAS oncogenes: weaving a tumorigenic web

    PubMed Central

    Pylayeva-Gupta, Yuliya; Grabocka, Elda; Bar-Sagi, Dafna

    2013-01-01

    RAS proteins are essential components of signalling pathways that emanate from cell surface receptors. Oncogenic activation of these proteins owing to missense mutations is frequently detected in several types of cancer. A wealth of biochemical and genetic studies indicates that RAS proteins control a complex molecular circuitry that consists of a wide array of interconnecting pathways. In this Review, we describe how RAS oncogenes exploit their extensive signalling reach to affect multiple cellular processes that drive tumorigenesis. PMID:21993244

  10. Simulation Tools Model Icing for Aircraft Design

    NASA Technical Reports Server (NTRS)

    2012-01-01

    Here s a simple science experiment to try: Place an unopened bottle of distilled water in your freezer. After 2-3 hours, if the water is pure enough, you will notice that it has not frozen. Carefully pour the water into a bowl with a piece of ice in it. When it strikes the ice, the water will instantly freeze. One of the most basic and commonly known scientific facts is that water freezes at around 32 F. But this is not always the case. Water lacking any impurities for ice crystals to form around can be supercooled to even lower temperatures without freezing. High in the atmosphere, water droplets can achieve this delicate, supercooled state. When a plane flies through clouds containing these droplets, the water can strike the airframe and, like the supercooled water hitting the ice in the experiment above, freeze instantly. The ice buildup alters the aerodynamics of the plane - reducing lift and increasing drag - affecting its performance and presenting a safety issue if the plane can no longer fly effectively. In certain circumstances, ice can form inside aircraft engines, another potential hazard. NASA has long studied ways of detecting and countering atmospheric icing conditions as part of the Agency s efforts to enhance aviation safety. To do this, the Icing Branch at Glenn Research Center utilizes a number of world-class tools, including the Center s Icing Research Tunnel and the NASA 607 icing research aircraft, a "flying laboratory" for studying icing conditions. The branch has also developed a suite of software programs to help aircraft and icing protection system designers understand the behavior of ice accumulation on various surfaces and in various conditions. One of these innovations is the LEWICE ice accretion simulation software. Initially developed in the 1980s (when Glenn was known as Lewis Research Center), LEWICE has become one of the most widely used tools in icing research and aircraft design and certification. LEWICE has been transformed over

  11. Ras trafficking, localization and compartmentalized signalling

    PubMed Central

    Prior, Ian A.; Hancock, John F.

    2012-01-01

    Ras proteins are proto-oncogenes that are frequently mutated in human cancers. Three closely related isoforms, HRAS, KRAS and NRAS, are expressed in all cells and have overlapping but distinctive functions. Recent work has revealed how differences between the Ras isoforms in their trafficking, localization and protein-membrane orientation enable signalling specificity to be determined. We review the various strategies used to characterize compartmentalized Ras localization and signalling. Localization is an important contextual modifier of signalling networks and insights from the Ras system are of widespread relevance for researchers interested in signalling initiated from membranes. PMID:21924373

  12. Suppression of ras-transformants (review).

    PubMed

    Kuzumaki, N

    1991-01-01

    Transforming ras genes are the oncogenes most frequently identified in human cancers. This justifies the intense interest in finding ways to suppress oncogenicity in these gene family-mediated transformants. The methods of suppression can be classified as 1) genetical, 2) biological and 3) pharmacological. Most of the reagents used for the suppression inhibit rodent transformants induced by transfected viral or activated cellular ras oncogenes, but some of the reagents are also effective when applied to natural human transformants that contain activated ras oncogenes. The growth and tumorigenicity of the ras-transformants are suppressed by the inhibition of the integration, transcription, translation or post-translational modification of the ras genes and p21 ras proteins, as well as the inhibition of the expression of genes which collaborate in the ras-transformation or the enhancement of some tumor suppressor genes. These observations offer novel approaches to the investigation of malignant transformation by ras-oncogenes, and have potential application in treatment of ras-oncogene-induced tumors. PMID:2018365

  13. Telecom Link--A Competitive Simulated Design Exercise.

    ERIC Educational Resources Information Center

    Freeman, J.; Allen, J.

    1982-01-01

    Telecom link is a structured design exercise concerned with building a telecommunications link between London and Amsterdam. Designed for A-level physics, the simulation requires a minimum of 10 hours. Aims of the exercise, design specifications and technical aspects, and summaries of four possible technologies used in the simulation are…

  14. Designing with Ada for satellite simulation: A case study

    NASA Technical Reports Server (NTRS)

    Agresti, W. W.; Church, V. E.; Card, D. N.; Lo, P. L.

    1986-01-01

    A FORTRAN oriented and an Ada oriented design for the same system are compared to learn whether an essentially different design was produced using Ada. The designs were produced by an experiment that involves the parallel development of software for a spacecraft dynamics simulator. Design differences are identified in the use of abstractions, system structure, and simulator operations. Although the designs were vastly different, this result may be influenced by some special characteristics discussed.

  15. Designing with Ada for satellite simulation: A case study

    NASA Technical Reports Server (NTRS)

    Agresti, William W.; Church, Victor E.; Card, David N.; Lo, P. L.

    1986-01-01

    A FORTRAN-operated and an Ada-oriented design for the same system are compared to learn whether an essentially different design was produced using Ada. The designs were produced by an experiment that involves the parallel development of software for a spacecraft dynamics simulator. Design differences are identified in the use of abstractions, system structure, and simulator operations. Although the designs were significantly different, this result may be influenced by some special characteristics discussed.

  16. Expression, Purification, and Characterization of Ras Protein (BmRas1) from Bombyx mori

    PubMed Central

    Quan, Yanping; Liu, Guangqiang; Yu, Wei; Nie, Zuoming; Chen, Jian; Lv, Zhengbing; Zhang, Yaozhou

    2012-01-01

    The Ras subfamily is the member of small G proteins superfamily involved in cellular signal transduction. Activation of Ras signaling causes cell growth, differentiation, and survival. Bombyx mori Ras-like protein (BmRas1) may belong to the Ras subfamily. It contained an H-N-K-Ras-like domain. The BmRas1 mRNA consisted of 1459 bp. The open reading frame contained 579 bp, encoding 192 amino acids. The protein had such secondary structures as α-helices, extended strand, and random coil. BmRas1 was expressed successfully in E. coli BL21. The recombinant protein was purified with metal-chelating affinity chromatography. The GTPase activity of purified protein was determined by FeSO4-(NH4)2MoO4 assay. The results showed that purified recombinant protein had intrinsic activity of GTPase. High titer polyclonal antibodies were generated by New Zealand rabbit immunized with purified protein. The gene expression features of BmRas1 at different stages and in different organs of the fifth instar larvae were analyzed by Western blot. The results showed that BmRas1 was expressed highly in three development stages including egg, pupae, and adult, but low expression in larva. BmRas1 was expressed in these tissues including head, malpighian tubule, genital gland, and silk gland. The purified recombinant protein would be utilized to further function studies of BmRas1. PMID:22536118

  17. Analysis of Binding Site Hot Spots on the Surface of Ras GTPase

    PubMed Central

    Buhrman, Greg; O’Connor, Casey; Zerbe, Brandon; Kearney, Bradley M.; Napoleon, Raeanne; Kovrigina, Elizaveta A.; Vajda, Sandor; Kozakov, Dima; Kovrigin, Evgenii L.; Mattos, Carla

    2011-01-01

    We have recently discovered an allosteric switch in Ras, bringing an additional level of complexity to this GTPase whose mutants are involved in nearly 30% of cancers. Upon activation of the allosteric switch, there is a shift in helix 3/loop 7 associated with a disorder to order transition in the active site. Here, we use a combination of multiple solvent crystal structures and computational solvent mapping (FTMap) to determine binding site hot spots in the “off” and “on” allosteric states of the GTP-bound form of H-Ras. Thirteen sites are revealed, expanding possible target sites for ligand binding well beyond the active site. Comparison of FTMaps for the H and K isoforms reveals essentially identical hot spots. Furthermore, using NMR measurements of spin relaxation, we determined that K-Ras exhibits global conformational dynamics very similar to those we previously reported for H-Ras. We thus hypothesize that the global conformational rearrangement serves as a mechanism for allosteric coupling between the effector interface and remote hot spots in all Ras isoforms. At least with respect to the binding sites involving the G domain, H-Ras is an excellent model for K-Ras and probably N-Ras as well. Ras has so far been elusive as a target for drug design. The present work identifies various unexplored hot spots throughout the entire surface of Ras, extending the focus from the disordered active site to well-ordered locations that should be easier to target. PMID:21945529

  18. Design and simulation of lithium rechargeable batteries

    SciTech Connect

    Doyle, C.M.

    1995-08-01

    Lithium -based rechargeable batteries that utilize insertion electrodes are being considered for electric-vehicle applications because of their high energy density and inherent reversibility. General mathematical models are developed that apply to a wide range of lithium-based systems, including the recently commercialized lithium-ion cell. The modeling approach is macroscopic, using porous electrode theory to treat the composite insertion electrodes and concentrated solution theory to describe the transport processes in the solution phase. The insertion process itself is treated with a charge-transfer process at the surface obeying Butler-Volmer kinetics, followed by diffusion of the lithium ion into the host structure. These models are used to explore the phenomena that occur inside of lithium cells under conditions of discharge, charge, and during periods of relaxation. Also, in order to understand the phenomena that limit the high-rate discharge of these systems, we focus on the modeling of a particular system with well-characterized material properties and system parameters. The system chosen is a lithium-ion cell produced by Bellcore in Red Bank, NJ, consisting of a lithium-carbon negative electrode, a plasticized polymer electrolyte, and a lithium-manganese-oxide spinel positive electrode. This battery is being marketed for consumer electronic applications. The system is characterized experimentally in terms of its transport and thermodynamic properties, followed by detailed comparisons of simulation results with experimental discharge curves. Next, the optimization of this system for particular applications is explored based on Ragone plots of the specific energy versus average specific power provided by various designs.

  19. The Structural Basis of Oncogenic Mutations G12, G13 and Q61 in Small GTPase K-Ras4B

    PubMed Central

    Lu, Shaoyong; Jang, Hyunbum; Nussinov, Ruth; Zhang, Jian

    2016-01-01

    Ras mediates cell proliferation, survival and differentiation. Mutations in K-Ras4B are predominant at residues G12, G13 and Q61. Even though all impair GAP-assisted GTP → GDP hydrolysis, the mutation frequencies of K-Ras4B in human cancers vary. Here we aim to figure out their mechanisms and differential oncogenicity. In total, we performed 6.4 μs molecular dynamics simulations on the wild-type K-Ras4B (K-Ras4BWT-GTP/GDP) catalytic domain, the K-Ras4BWT-GTP–GAP complex, and the mutants (K-Ras4BG12C/G12D/G12V-GTP/GDP, K-Ras4BG13D-GTP/GDP, K-Ras4BQ61H-GTP/GDP) and their complexes with GAP. In addition, we simulated ‘exchanged’ nucleotide states. These comprehensive simulations reveal that in solution K-Ras4BWT-GTP exists in two, active and inactive, conformations. Oncogenic mutations differentially elicit an inactive-to-active conformational transition in K-Ras4B-GTP; in K-Ras4BG12C/G12D-GDP they expose the bound nucleotide which facilitates the GDP-to-GTP exchange. These mechanisms may help elucidate the differential mutational statistics in K-Ras4B-driven cancers. Exchanged nucleotide simulations reveal that the conformational transition is more accessible in the GTP-to-GDP than in the GDP-to-GTP exchange. Importantly, GAP not only donates its R789 arginine finger, but stabilizes the catalytically-competent conformation and pre-organizes catalytic residue Q61; mutations disturb the R789/Q61 organization, impairing GAP-mediated GTP hydrolysis. Together, our simulations help provide a mechanistic explanation of key mutational events in one of the most oncogenic proteins in cancer. PMID:26902995

  20. Ras-Mediated Deregulation of the Circadian Clock in Cancer

    PubMed Central

    Relógio, Angela; Thomas, Philippe; Medina-Pérez, Paula; Reischl, Silke; Bervoets, Sander; Gloc, Ewa; Riemer, Pamela; Mang-Fatehi, Shila; Maier, Bert; Schäfer, Reinhold; Leser, Ulf; Herzel, Hanspeter; Kramer, Achim; Sers, Christine

    2014-01-01

    Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock. PMID:24875049

  1. Ras-mediated deregulation of the circadian clock in cancer.

    PubMed

    Relógio, Angela; Thomas, Philippe; Medina-Pérez, Paula; Reischl, Silke; Bervoets, Sander; Gloc, Ewa; Riemer, Pamela; Mang-Fatehi, Shila; Maier, Bert; Schäfer, Reinhold; Leser, Ulf; Herzel, Hanspeter; Kramer, Achim; Sers, Christine

    2014-01-01

    Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock. PMID:24875049

  2. AVCS Simulator Test Plan and Design Guide

    NASA Technical Reports Server (NTRS)

    Shelden, Stephen

    2001-01-01

    Internal document for communication of AVCS direction and documentation of simulator functionality. Discusses methods for AVCS simulation evaluation of pilot functions, implementation strategy of varying functional representation of pilot tasks (by instantiations of a base AVCS to reasonably approximate the interface of various vehicles -- e.g. Altair, GlobalHawk, etc.).

  3. Phobos: Simulation-Driven Design for Exploration

    NASA Technical Reports Server (NTRS)

    Crues, Edwin

    2015-01-01

    Dr. Edwin "Zack" Crues presented an overview of the current use of modeling and simulation technologies by the NASA Exploration Systems Simulations (NExSyS) team in investigating the spacecraft and missions for the human exploration of Mars' moon Phobos.

  4. Differential activation of yeast adenylyl cyclase by Ras1 and Ras2 depends on the conserved N terminus.

    PubMed

    Hurwitz, N; Segal, M; Marbach, I; Levitzki, A

    1995-11-21

    Although both Ras1 and Ras2 activate adenylyl cyclase in yeast, a number of differences can be observed regarding their function in the cAMP pathway. To explore the relative contribution of conserved and variable domains in determining these differences, chimeric RAS1-RAS2 or RAS2-RAS1 genes were constructed by swapping the sequences encoding the variable C-terminal domains. These constructs were expressed in a cdc25ts ras1 ras2 strain. Biochemical data show that the difference in efficacy of adenylyl cyclase activation between the two Ras proteins resides in the highly conserved N-terminal domain. This finding is supported by the observation that Ras2 delta, in which the C-terminal domain of Ras2 has been deleted, is a more potent activator of the yeast adenylyl cyclase than Ras1 delta, in which the C-terminal domain of Ras1 has been deleted. These observations suggest that amino acid residues other than the highly conserved residues of the effector domain within the N terminus may determine the efficiency of functional interaction with adenylyl cyclase. Similar levels of intracellular cAMP were found in Ras1, Ras1-Ras2, Ras1 delta, Ras2, and Ras2-Ras1 strains throughout the growth curve. This was found to result from the higher expression of Ras1 and Ras1-Ras2, which compensate for their lower efficacy in activating adenylyl cyclase. These results suggest that the difference between the Ras1 and the Ras2 phenotype is not due to their different efficacy in activating the cAMP pathway and that the divergent C-terminal domains are responsible for these differences, through interaction with other regulatory elements. PMID:7479926

  5. Optimizing depuration of salmon in RAS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fish cultured within water recirculating aquaculture systems (RAS) can acquire "earthy" or "musty" off-flavors due to bioaccumulation of the compounds geosmin and 2-methylisoborneol (MIB), respectively, which are produced by certain bacterial species present in RAS biosolids and microbial biofilms. ...

  6. Established and emerging fluorescence-based assays for G-protein function: Ras-superfamily GTPases.

    PubMed

    Rojas, Rafael J; Kimple, Randall J; Rossman, Kent L; Siderovski, David P; Sondek, John

    2003-06-01

    Ras and Rho GTPases are signaling proteins that regulate a variety of physiological events and are intimately linked to the progression of cancer. Recently, a variety of fluorescence-based assays have been refined to monitor activation of these GTPases. This review summarizes current fluorescence-based techniques for studying Ras superfamily GTPases with an emphasis on practical examples and high-throughput applications. These techniques are not only useful for biochemical characterization of Ras superfamily members, but will also facilitate the discovery of small molecule therapeutics designed to inhibit signal transduction mediated by GTPases. PMID:12769685

  7. Integrated simulation environment for lighting design

    SciTech Connect

    Pal, Vineeta; Papamichael, Konstantinos

    2001-05-24

    Lighting design involves the consideration of multiple performance criteria, from the earliest stages of conceptual design, through various stages of controls and operation in a project's life cycle. These criteria include: (1) the quantitative analysis of illuminance and luminance distribution due to daylighting and electric lighting; (2) qualitative analysis of the lighting design with photometrically accurate renderings of the designed environment; (3) analysis of energy implications of daylighting and electric lighting design and operation;, and (4) analysis of control strategies and sensor placement for maximizing energy savings from lighting control while providing visual comfort. In this paper we describe the development of an integrated decision-making environment that brings together several different tools, and provides the data management and process control required for a multi-criterion support of the design and operation of daylighting and electric lighting systems. The result is a powerful design and decision-making environment to meet the diverse and evolving needs of lighting designers and operators.

  8. Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1

    PubMed Central

    Iwig, Jeffrey S; Vercoulen, Yvonne; Das, Rahul; Barros, Tiago; Limnander, Andre; Che, Yan; Pelton, Jeffrey G; Wemmer, David E; Roose, Jeroen P; Kuriyan, John

    2013-01-01

    RasGRP1 and SOS are Ras-specific nucleotide exchange factors that have distinct roles in lymphocyte development. RasGRP1 is important in some cancers and autoimmune diseases but, in contrast to SOS, its regulatory mechanisms are poorly understood. Activating signals lead to the membrane recruitment of RasGRP1 and Ras engagement, but it is unclear how interactions between RasGRP1 and Ras are suppressed in the absence of such signals. We present a crystal structure of a fragment of RasGRP1 in which the Ras-binding site is blocked by an interdomain linker and the membrane-interaction surface of RasGRP1 is hidden within a dimerization interface that may be stabilized by the C-terminal oligomerization domain. NMR data demonstrate that calcium binding to the regulatory module generates substantial conformational changes that are incompatible with the inactive assembly. These features allow RasGRP1 to be maintained in an inactive state that is poised for activation by calcium and membrane-localization signals. DOI: http://dx.doi.org/10.7554/eLife.00813.001 PMID:23908768

  9. A New View of Ras Isoforms in Cancers.

    PubMed

    Nussinov, Ruth; Tsai, Chung-Jung; Chakrabarti, Mayukh; Jang, Hyunbum

    2016-01-01

    Does small GTPase K-Ras4A have a single state or two states, one resembling K-Ras4B and the other N-Ras? A recent study of K-Ras4A made the remarkable observation that even in the absence of the palmitoyl, K-Ras4A can be active at the plasma membrane. Importantly, this suggests that K-Ras4A may exist in two distinct signaling states. In state 1, K-Ras4A is only farnesylated, like K-Ras4B; in state 2, farnesylated and palmitoylated, like N-Ras. The K-Ras4A hypervariable region sequence is positively charged, in between K-Ras4B and N-Ras. Taken together, this raises the possibility that the farnesylated but nonpalmitoylated state 1, like K-Ras4B, binds calmodulin and is associated with colorectal and other adenocarcinomas like lung cancer and pancreatic ductal adenocarcinoma. On the other hand, state 2 may be associated with melanoma and other cancers where N-Ras is a major contributor, such as acute myeloid leukemia. Importantly, H-Ras has two, singly and doubly, palmitoylated states that may also serve distinct functional roles. The multiple signaling states of palmitoylated Ras isoforms question the completeness of small GTPase Ras isoform statistics in different cancer types and call for reevaluation of concepts and protocols. They may also call for reconsideration of oncogenic Ras therapeutics. PMID:26659836

  10. Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

    PubMed Central

    Cox, Adrienne D.; Der, Channing J.; Philips, Mark R.

    2015-01-01

    RAS proteins require membrane association for their biological activity, making this association a logical target for anti-RAS therapeutics. Lipid modification of RAS proteins by a farnesyl isoprenoid is an obligate step in that association, and is an enzymatic process. Accordingly, farnesyltransferase inhibitors (FTIs) were developed as potential anti-RAS drugs. The lack of efficacy of FTIs as anti-cancer drugs was widely seen as indicating that blocking RAS membrane association was a flawed approach to cancer treatment. However, a deeper understanding of RAS modification and trafficking has revealed that this was an erroneous conclusion. In the presence of FTIs, KRAS and NRAS, which are the RAS isoforms most frequently mutated in cancer, become substrates for alternative modification, can still associate with membranes, and can still function. Thus, FTIs failed not because blocking RAS membrane association is an ineffective approach, but because FTIs failed to accomplish that task. Recent findings regarding RAS isoform trafficking and the regulation of RAS subcellular localization have rekindled interest in efforts to target these processes. In particular, improved understanding of the palmitoylation/depalmitoylation cycle that regulates RAS interaction with the plasma membrane, endomembranes and cytosol, and of the potential importance of RAS chaperones, have led to new approaches. Efforts to validate and target other enzymatically regulated post-translational modifications are also ongoing. In this review, we revisit lessons learned, describe the current state of the art, and highlight challenging but promising directions to achieve the goal of disrupting RAS membrane association and subcellular localization for anti-RAS drug development. PMID:25878363

  11. Some Current Problems in Simulator Design, Testing and Use.

    ERIC Educational Resources Information Center

    Caro, Paul W.

    Concerned with the general problem of the effectiveness of simulator training, this report reflects information developed during the conduct of aircraft simulator training research projects sponsored by the Air Force, Army, Navy, and Coast Guard. Problems are identified related to simulator design, testing, and use, all of which impact upon…

  12. Mechanical design of NASA Ames Research Center vertical motion simulator

    NASA Technical Reports Server (NTRS)

    Engelbert, D. F.; Bakke, A. P.; Chargin, M. K.; Vallotton, W. C.

    1976-01-01

    NASA has designed and is constructing a new flight simulator with large vertical travel. Several aspects of the mechanical design of this Vertical Motion Simulator (VMS) are discussed, including the multiple rack and pinion vertical drive, a pneumatic equilibration system, and the friction-damped rigid link catenaries used as cable supports.

  13. Automated simulation as part of a design workstation

    NASA Technical Reports Server (NTRS)

    Cantwell, Elizabeth; Shenk, T.; Robinson, P.; Upadhye, R.

    1990-01-01

    A development project for a design workstation for advanced life-support systems (called the DAWN Project, for Design Assistant Workstation), incorporating qualitative simulation, required the implementation of a useful qualitative simulation capability and the integration of qualitative and quantitative simulation such that simulation capabilities are maximized without duplication. The reason is that to produce design solutions to a system goal, the behavior of the system in both a steady and perturbed state must be represented. The Qualitative Simulation Tool (QST), on an expert-system-like model building and simulation interface toll called ScratchPad (SP), and on the integration of QST and SP with more conventional, commercially available simulation packages now being applied in the evaluation of life-support system processes and components are discussed.

  14. M-Ras induces Ral and JNK activation to regulate MEK/ERK-independent gene expression in MCF-7 breast cancer cells

    PubMed Central

    Castro, Ariel F.; Campos, Tania; Babcock, Justin T.; Armijo, Marisol E.; Martinez-Conde, Alfonso; Pincheira, Roxana; Quilliam, Lawrence A.

    2011-01-01

    Constitutive activation of M-Ras has previously been reported to cause morphologic and growth transformation of murine cells, suggesting that M-Ras plays a role in tumorigenesis. Cell transformation by M-Ras correlated with weak activation of the Raf/MEK/ERK pathway, although contributions from other downstream effectors were suggested. Recent studies indicate that signaling events distinct from the Raf/MEK/ERK cascade are critical for human tumorigenesis. However, it is unknown what signaling events M-Ras triggers in human cells. Using constitutively active M-Ras (Q71L) containing additional mutations within its effector binding loop, we found that M-Ras induces MEK/ERK-dependent and -independent Elk1 activation as well as PI3K/Akt and JNK/cJun activation in human MCF-7 breast cancer cells. Among several human cell lines examined, M-Ras-induced MEK/ERK-independent Elk1 activation was only detected in MCF-7 cells, and correlated with Rlf /M-Ras interaction and Ral /JNK activation. Supporting a role for M-Ras signaling in breast cancer, EGF activated M-Ras and promoted its interaction with endogenous Rlf. In addition, constitutive activation of M-Ras induced estrogen-independent growth of MCF-7 cells that was dependent on PI3K/Akt, MEK/ERK and JNK activation. Thus, our studies demonstrate that M-Ras signaling activity differs between human cells, highlighting the importance of defining Ras protein signaling within each cell type, especially when designing treatments for Ras-induced cancer. These findings also demonstrate that M-Ras activity may be important for progression of EGFR-dependent tumors. PMID:22121046

  15. Simulation Packages Expand Aircraft Design Options

    NASA Technical Reports Server (NTRS)

    2013-01-01

    In 2001, NASA released a new approach to computational fluid dynamics that allows users to perform automated analysis on complex vehicle designs. In 2010, Palo Alto, California-based Desktop Aeronautics acquired a license from Ames Research Center to sell the technology. Today, the product assists organizations in the design of subsonic aircraft, space planes, spacecraft, and high speed commercial jets.

  16. Design and Simulation of MEMS Enabled Systems

    NASA Astrophysics Data System (ADS)

    da Silva, Mark

    2001-03-01

    Over the past two decades considerable progress in microsystems (MEMS) fabrication technologies has been made resulting in a variety of commercially successful devices. Most of these devices have required application specific fabrication steps, which must be developed, and the lack of proper design tools often resulted in repeated prototyping that was expensive and time consuming. Further development of MEMS enabled commercial products and reduction of the time to market requires implementation of a concurrent design methodology through better design tools and standardization of the fabrication processes. The cross-disciplinary nature of MEMS-Enabled Systems necessitates designers with different backgrounds to work together in understanding the effects of one sub-system on another and this requires a top-down approach to integrated system design. Design tools that can facilitate this communication and reduce the need for excessive prototype fabrication and test iterations and significantly reduce cost and time-to-market are vitally important. The main focus of this article is to describe the top-down design methodology and and ongoing research on tools that facilitate concurrent design of MEMS enabled systems.

  17. Optimum spaceborne computer system design by simulation

    NASA Technical Reports Server (NTRS)

    Williams, T.; Kerner, H.; Weatherbee, J. E.; Taylor, D. S.; Hodges, B.

    1973-01-01

    A deterministic simulator is described which models the Automatically Reconfigurable Modular Multiprocessor System (ARMMS), a candidate computer system for future manned and unmanned space missions. Its use as a tool to study and determine the minimum computer system configuration necessary to satisfy the on-board computational requirements of a typical mission is presented. The paper describes how the computer system configuration is determined in order to satisfy the data processing demand of the various shuttle booster subsytems. The configuration which is developed as a result of studies with the simulator is optimal with respect to the efficient use of computer system resources.

  18. Optimum spaceborne computer system design by simulation

    NASA Technical Reports Server (NTRS)

    Williams, T.; Weatherbee, J. E.; Taylor, D. S.

    1972-01-01

    A deterministic digital simulation model is described which models the Automatically Reconfigurable Modular Multiprocessor System (ARMMS), a candidate computer system for future manned and unmanned space missions. Use of the model as a tool in configuring a minimum computer system for a typical mission is demonstrated. The configuration which is developed as a result of studies with the simulator is optimal with respect to the efficient use of computer system resources, i.e., the configuration derived is a minimal one. Other considerations such as increased reliability through the use of standby spares would be taken into account in the definition of a practical system for a given mission.

  19. Space shuttle visual simulation system design study

    NASA Technical Reports Server (NTRS)

    1973-01-01

    The current and near-future state-of-the-art in visual simulation equipment technology is related to the requirements of the space shuttle visual system. Image source, image sensing, and displays are analyzed on a subsystem basis, and the principal conclusions are used in the formulation of a recommended baseline visual system. Perceptibility and visibility are also analyzed.

  20. RAS Interaction with PI3K

    PubMed Central

    Castellano, Esther; Downward, Julian

    2011-01-01

    RAS proteins are small GTPases known for their involvement in oncogenesis: around 25% of human tumors present mutations in a member of this family. RAS operates in a complex signaling network with multiple activators and effectors, which allows them to regulate many cellular functions such as cell proliferation, differentiation, apoptosis, and senescence. Phosphatidylinositol 3-kinase (PI3K) is one of the main effector pathways of RAS, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. However, it is the involvement of this pathway in human tumors that has attracted most attention. PI3K has proven to be necessary for RAS-induced transformation in vitro, and more importantly, mice with mutations in the PI3K catalytic subunit p110α that block its ability to interact with RAS are highly resistant to endogenous oncogenic KRAS-induced lung tumorigenesis and HRAS-induced skin carcinogenesis. These animals also have a delayed development of the lymphatic vasculature. Many PI3K inhibitors have been developed that are now in clinical trials. However, it is a complex pathway with many feedback loops, and interactions with other pathways make the results of its inhibition hard to predict. Combined therapy with another RAS-regulated pathway such as RAF/MEK/ERK may be the most effective way to treat cancer, at least in animal models mimicking the human disease. In this review, we will summarize current knowledge about how RAS regulates one of its best-known effectors, PI3K. PMID:21779497

  1. An HLA based design of space system simulation environment

    NASA Astrophysics Data System (ADS)

    Li, Yinghua; Li, Yong; Liu, Jie

    2007-06-01

    Space system simulation is involved in many application fields, such as space remote sensing and space communication, etc. A simulation environment which can be shared by different space system simulation is needed. Two rules, called object template towing and hierarchical reusability, are proposed. Based on these two rules, the architecture, the network structure and the function structure of the simulation environment are designed. Then, the mechanism of utilizing data resources, inheriting object models and running simulation systems are also constructed. These mechanisms make the simulation objects defined in advance be easily inherited by different HLA federates, the fundamental simulation models be shared by different simulation systems. Therefore, the simulation environment is highly universal and reusable.

  2. Metabolic Dependencies in RAS-Driven Cancers.

    PubMed

    Kimmelman, Alec C

    2015-04-15

    The ability to inhibit the RAS oncogene has been the holy grail of oncology because of the critical role of this gene in a multitude of tumor types. In addition, RAS-mutant tumors are among the most aggressive and refractory to treatment. Although directly targeting the RAS oncogene has proven challenging, an alternative approach for treating RAS-driven cancers is to inhibit critical downstream events that are required for tumor maintenance. Indeed, much focus has been put on inhibiting signaling cascades downstream of RAS. Recent studies have shown that oncogenic RAS promotes a metabolic reprogramming of tumor cells, shifting them toward an anabolic metabolism necessary to produce biomass to support unconstrained proliferation. These cancers also use a diverse set of fuel sources to meet their metabolic needs and have even developed a variety of mechanisms to act as metabolic scavengers to obtain necessary metabolic substrates from both extracellular and intracellular sources. Collectively, these adaptations can create "metabolic bottlenecks" whereby tumor cells rely on particular pathways or rate-limiting metabolites. In this regard, inhibiting individual or combinations of these metabolic pathways can attenuate growth in preclinical models. Because these dependencies are tumor selective and downstream of oncogenic RAS, there is the opportunity for therapeutic intervention. Although targeting tumor metabolism is still in the early days of translation to patients, our continued advances in understanding critical metabolic adaptations in RAS-driven cancers, as well as the ability to study this altered metabolism in relevant tumor models, will accelerate the development of new therapeutic approaches. Clin Cancer Res; 21(8); 1828-34. ©2015 AACR. See all articles in this CCR Focus section, "Targeting RAS-Driven Cancers." PMID:25878364

  3. Monitoring Ras Interactions with the Nucleotide Exchange Factor Son of Sevenless (Sos) Using Site-specific NMR Reporter Signals and Intrinsic Fluorescence*

    PubMed Central

    Vo, Uybach; Vajpai, Navratna; Flavell, Liz; Bobby, Romel; Breeze, Alexander L.; Embrey, Kevin J.; Golovanov, Alexander P.

    2016-01-01

    The activity of Ras is controlled by the interconversion between GTP- and GDP-bound forms partly regulated by the binding of the guanine nucleotide exchange factor Son of Sevenless (Sos). The details of Sos binding, leading to nucleotide exchange and subsequent dissociation of the complex, are not completely understood. Here, we used uniformly 15N-labeled Ras as well as [13C]methyl-Met,Ile-labeled Sos for observing site-specific details of Ras-Sos interactions in solution. Binding of various forms of Ras (loaded with GDP and mimics of GTP or nucleotide-free) at the allosteric and catalytic sites of Sos was comprehensively characterized by monitoring signal perturbations in the NMR spectra. The overall affinity of binding between these protein variants as well as their selected functional mutants was also investigated using intrinsic fluorescence. The data support a positive feedback activation of Sos by Ras·GTP with Ras·GTP binding as a substrate for the catalytic site of activated Sos more weakly than Ras·GDP, suggesting that Sos should actively promote unidirectional GDP → GTP exchange on Ras in preference of passive homonucleotide exchange. Ras·GDP weakly binds to the catalytic but not to the allosteric site of Sos. This confirms that Ras·GDP cannot properly activate Sos at the allosteric site. The novel site-specific assay described may be useful for design of drugs aimed at perturbing Ras-Sos interactions. PMID:26565026

  4. Monitoring Ras Interactions with the Nucleotide Exchange Factor Son of Sevenless (Sos) Using Site-specific NMR Reporter Signals and Intrinsic Fluorescence.

    PubMed

    Vo, Uybach; Vajpai, Navratna; Flavell, Liz; Bobby, Romel; Breeze, Alexander L; Embrey, Kevin J; Golovanov, Alexander P

    2016-01-22

    The activity of Ras is controlled by the interconversion between GTP- and GDP-bound forms partly regulated by the binding of the guanine nucleotide exchange factor Son of Sevenless (Sos). The details of Sos binding, leading to nucleotide exchange and subsequent dissociation of the complex, are not completely understood. Here, we used uniformly (15)N-labeled Ras as well as [(13)C]methyl-Met,Ile-labeled Sos for observing site-specific details of Ras-Sos interactions in solution. Binding of various forms of Ras (loaded with GDP and mimics of GTP or nucleotide-free) at the allosteric and catalytic sites of Sos was comprehensively characterized by monitoring signal perturbations in the NMR spectra. The overall affinity of binding between these protein variants as well as their selected functional mutants was also investigated using intrinsic fluorescence. The data support a positive feedback activation of Sos by Ras·GTP with Ras·GTP binding as a substrate for the catalytic site of activated Sos more weakly than Ras·GDP, suggesting that Sos should actively promote unidirectional GDP → GTP exchange on Ras in preference of passive homonucleotide exchange. Ras·GDP weakly binds to the catalytic but not to the allosteric site of Sos. This confirms that Ras·GDP cannot properly activate Sos at the allosteric site. The novel site-specific assay described may be useful for design of drugs aimed at perturbing Ras-Sos interactions. PMID:26565026

  5. Design and Test of Advanced Thermal Simulators for an Alkali Metal-Cooled Reactor Simulator

    NASA Technical Reports Server (NTRS)

    Garber, Anne E.; Dickens, Ricky E.

    2011-01-01

    The Early Flight Fission Test Facility (EFF-TF) at NASA Marshall Space Flight Center (MSFC) has as one of its primary missions the development and testing of fission reactor simulators for space applications. A key component in these simulated reactors is the thermal simulator, designed to closely mimic the form and function of a nuclear fuel pin using electric heating. Continuing effort has been made to design simple, robust, inexpensive thermal simulators that closely match the steady-state and transient performance of a nuclear fuel pin. A series of these simulators have been designed, developed, fabricated and tested individually and in a number of simulated reactor systems at the EFF-TF. The purpose of the thermal simulators developed under the Fission Surface Power (FSP) task is to ensure that non-nuclear testing can be performed at sufficiently high fidelity to allow a cost-effective qualification and acceptance strategy to be used. Prototype thermal simulator design is founded on the baseline Fission Surface Power reactor design. Recent efforts have been focused on the design, fabrication and test of a prototype thermal simulator appropriate for use in the Technology Demonstration Unit (TDU). While designing the thermal simulators described in this paper, effort were made to improve the axial power profile matching of the thermal simulators. Simultaneously, a search was conducted for graphite materials with higher resistivities than had been employed in the past. The combination of these two efforts resulted in the creation of thermal simulators with power capacities of 2300-3300 W per unit. Six of these elements were installed in a simulated core and tested in the alkali metal-cooled Fission Surface Power Primary Test Circuit (FSP-PTC) at a variety of liquid metal flow rates and temperatures. This paper documents the design of the thermal simulators, test program, and test results.

  6. Physiological Based Simulator Fidelity Design Guidance

    NASA Technical Reports Server (NTRS)

    Schnell, Thomas; Hamel, Nancy; Postnikov, Alex; Hoke, Jaclyn; McLean, Angus L. M. Thom, III

    2012-01-01

    The evolution of the role of flight simulation has reinforced assumptions in aviation that the degree of realism in a simulation system directly correlates to the training benefit, i.e., more fidelity is always better. The construct of fidelity has several dimensions, including physical fidelity, functional fidelity, and cognitive fidelity. Interaction of different fidelity dimensions has an impact on trainee immersion, presence, and transfer of training. This paper discusses research results of a recent study that investigated if physiological-based methods could be used to determine the required level of simulator fidelity. Pilots performed a relatively complex flight task consisting of mission task elements of various levels of difficulty in a fixed base flight simulator and a real fighter jet trainer aircraft. Flight runs were performed using one forward visual channel of 40 deg. field of view for the lowest level of fidelity, 120 deg. field of view for the middle level of fidelity, and unrestricted field of view and full dynamic acceleration in the real airplane. Neuro-cognitive and physiological measures were collected under these conditions using the Cognitive Avionics Tool Set (CATS) and nonlinear closed form models for workload prediction were generated based on these data for the various mission task elements. One finding of the work described herein is that simple heart rate is a relatively good predictor of cognitive workload, even for short tasks with dynamic changes in cognitive loading. Additionally, we found that models that used a wide range of physiological and neuro-cognitive measures can further boost the accuracy of the workload prediction.

  7. Object oriented simulation implementation in support of robust system design

    SciTech Connect

    Not Available

    1993-04-01

    A very brief description of two ``classes`` developed for use in design optimization and sensitivity analyses are given. These classes are used in simulations of systems in early design phases as well as system response assessments. The instanciated classes were coupled to system models to demonstrate the practically and efficiency of using these objects in complex robust design processes.

  8. Optimal Living Environments for the Elderly: A Design Simulation Approach.

    ERIC Educational Resources Information Center

    Hoffman, Stephanie B.; And Others

    PLANNED AGE (Planned Alternatives for Gerontological Environments) is a consumer/advocate-oriented design simulation package that provides: (a) a medium for user-planner interaction in the design of living and service environments for the aged; (b) an educational, planning, design, and evaluation tool that can be used by the elderly, their…

  9. JEFF: Air transport system design simulation

    NASA Technical Reports Server (NTRS)

    1992-01-01

    Jeff is a remotely piloted vehicle designed by the Blue Team, a division of AE441, Inc., to fulfill the mission proposed by G-Dome Enterprises: to build a cost efficient aircraft to service Aeroworld with overnight cargo delivery. The design of Jeff was most significantly influenced by the need to minimize costs. This objective was pursued by building fewer large planes as opposed to many small planes. Thus, by building an aircraft with a large payload capacity, G-Dome Enterprises will be able to minimize the large costs and the large number of cycles that are associated with a large fleet. Another factor which had a significant influence on our design was the constraint that our design had to fit into a 2'x2'x5' storage container. This constraint meant that unless we wanted to build foldable wings that Jeff's span would be limited to 10 feet. Since this was not enough lifting surface to suit our needs a canard configuration was chosen to get the needed lifting surface and avoid the structural dilemma of foldable wings. The aircraft is constructed mainly of balsa, with spruce wing and canard spars and a monokote covering. It was designed to support a maximum payload weight of 35 oz. (total aircraft weight of 108 oz.) and withstand a maximum load factor of 2.5.

  10. Dynamics of adaptive structures: Design through simulations

    NASA Technical Reports Server (NTRS)

    Park, K. C.; Alexander, S.

    1993-01-01

    The use of a helical bi-morph actuator/sensor concept by mimicking the change of helical waveform in bacterial flagella is perhaps the first application of bacterial motions (living species) to longitudinal deployment of space structures. However, no dynamical considerations were analyzed to explain the waveform change mechanisms. The objective is to review various deployment concepts from the dynamics point of view and introduce the dynamical considerations from the outset as part of design considerations. Specifically, the impact of the incorporation of the combined static mechanisms and dynamic design considerations on the deployment performance during the reconfiguration stage is studied in terms of improved controllability, maneuvering duration, and joint singularity index. It is shown that intermediate configurations during articulations play an important role for improved joint mechanisms design and overall structural deployability.

  11. Scramjet Propulsive Flowpath Design and Numerical Simulation

    NASA Astrophysics Data System (ADS)

    Li, Jian-ping; Song, Wen-yan; Liu, Xin

    2014-06-01

    The integrated propulsive flowpath of scramjet configuration was preliminarily designed and analyzed in this paper. The flow-fields characteristics and performance of the designed two-dimensional integrated propulsive flowpath were numerically calculated under various equivalent fuel-air ratio conditions, using computational fluid dynamics methods. The calculation results were then compared with the experimental data on some typical conditions, and the flow-field and performance of the integrated scramjet flowpath with different equivalent fuel-air ratios were analyzed and discussed in detail. The investigation results from these efforts showed that: (1) the inlet function was beyond disturbances by combustion induced shock wave and pressure fluctuations under the equivalent fuel-air ratio condition of 1.0, which well satisfied the design requirements; (2) with the increasing equivalent fuel-air ratio, the combustion intensity in the combustor was significantly enhanced, resulting in an increasing net-thrust of the propulsive flowpath.

  12. Regulation of Ras Exchange Factors and Cellular Localization of Ras Activation by Lipid Messengers in T Cells

    PubMed Central

    Jun, Jesse E.; Rubio, Ignacio; Roose, Jeroen P.

    2013-01-01

    The Ras-MAPK signaling pathway is highly conserved throughout evolution and is activated downstream of a wide range of receptor stimuli. Ras guanine nucleotide exchange factors (RasGEFs) catalyze GTP loading of Ras and play a pivotal role in regulating receptor-ligand induced Ras activity. In T cells, three families of functionally important RasGEFs are expressed: RasGRF, RasGRP, and Son of Sevenless (SOS)-family GEFs. Early on it was recognized that Ras activation is critical for T cell development and that the RasGEFs play an important role herein. More recent work has revealed that nuances in Ras activation appear to significantly impact T cell development and selection. These nuances include distinct biochemical patterns of analog versus digital Ras activation, differences in cellular localization of Ras activation, and intricate interplays between the RasGEFs during distinct T cell developmental stages as revealed by various new mouse models. In many instances, the exact nature of these nuances in Ras activation or how these may result from fine-tuning of the RasGEFs is not understood. One large group of biomolecules critically involved in the control of RasGEFs functions are lipid second messengers. Multiple, yet distinct lipid products are generated following T cell receptor (TCR) stimulation and bind to different domains in the RasGRP and SOS RasGEFs to facilitate the activation of the membrane-anchored Ras GTPases. In this review we highlight how different lipid-based elements are generated by various enzymes downstream of the TCR and other receptors and how these dynamic and interrelated lipid products may fine-tune Ras activation by RasGEFs in developing T cells. PMID:24027568

  13. Advanced ERS design using computer simulation

    SciTech Connect

    Melhem, G.A.

    1995-12-31

    There are two schools of thought regarding pressure relief design, shortcut/simplified methods and detailed methods. The shortcut/simplified methods are mostly applicable to non-reactive systems. These methods use direct scale-up techniques to obtain a vent size. Little useful information can be obtained for reaction data such as onset temperatures, activation energy, decompositon stoichiometry, etc. In addition, this approach does not readily provide the ability to perform what-if and sensitivity analysis or data that can be used for post-release mitigation design. The detailed approach advocates a more fundamental approach to pressure relief design, especially for reactive systems. First, the reaction chemistry is qualified using small scale experiments and then this data is coupled with fluid dynamics to design the emergency relief system. In addition to vent sizing information, this approach provides insights into process modification and refinement as well as the establishment of a safe operating envelope. This approach provides necessary flow data for vent containment design (if required), structural support, etc. This approach also allows the direct evaluation of design sensitivity to variables such as temperature, pressure, composition, fill level, etc. on vent sizing while the shortcut approach requires an additional experiment per what-if scenario. This approach meets DIERS technology requirements for two-phase flow and vapor/liquid disengagement and exceeds it in many key areas for reacting systems such as stoichiometry estimation for decomposition reactions, non-ideal solutions effects, continuing reactions in piping and vent containment systems, etc. This paper provides an overview of our proposed equation of state based modeling approach and its computer code implementation. Numerous examples and model validations are also described. 42 refs., 23 figs., 9 tabs.

  14. Robust Design of Motor PWM Control using Modeling and Simulation

    NASA Astrophysics Data System (ADS)

    Zhan, Wei

    A robust design method is developed for Pulse Width Modulation (PWM) motor speed control. A first principle model for DC permanent magnetic motor is used to build a Simulink model for simulation and analysis. Based on the simulation result, the main factors that contributed to the average speed variation are identified using Design of Experiment (DOE). A robust solution is derived to reduce the aver age speed control variation using Response Surface Method (RSM). The robustness of the new design is verified using the simulation model.

  15. Pyrometry simulator (pyrosim) for diagnostic design.

    SciTech Connect

    Dolan, Daniel H., III

    2011-10-01

    Signal estimates are crucial to the design of time-resolved pyrometry measurements. These estimates affect fundamental design decisions, including the optical relay (fiber versus open beam), spectral range (visible or infrared), and amplification needs (possibly at the expense of time resolution). The pyrosim program makes such estimates, allowing the collected power, photon flux, and measured signal to be determined in a broad range of pyrometry measurements. Geometrical collection limits can be applied; sample emissivity, transfer efficiency, and detector sensitivity may also be specified, either as constants or functions of wavelength.

  16. Biochemical similarity of Schizosaccharomyces pombe ras1 protein with RAS2 protein of Saccharomyces cervisiae.

    PubMed

    Onozawa, T; Danjoh, I; Fujiyama, A

    1995-07-01

    Schizosaccharomyces pombe contains single ras oncogene homologue, ras1, that functions in the signal transduction pathway conducting the cell's mating processes. To understand the biochemical basis of yeast ras proteins, we have purified the ras1 protein and compared the major biochemical constants with those of RAS2 protein from Saccharomyces cerevisiae and mammalian ras proteins. The purified ras1 protein showed a remarkably high Kd value for GDP binding (178 nM) and for binding with ATP. In contrast, the Kd value for GTP binding and the rate of GTPase activity were 64 nM and 77 x 10(-6) s-1 at 37 degrees C, respectively; both were higher than normal p21ras protein, but at the same level as the RAS2 protein. We directly measured rate of GTP binding and GDP binding which were 3.9 x 10(-3) s-1 and 1.8 x 10(-3) s-1 at 30 degrees C, respectively. On the other hand, exchange rates between bound and free nucleotides remained almost constant throughout the tested combination of GTP and GDP, and were several-fold lower than the binding rate. These results suggest that the release of the guanine nucleotide is the rate-limiting step in the ras-GTP/GDP cycle. As a whole, the biochemical properties of the ras1 protein are close to those of the RAS2 protein, although these two proteins function differently in the signal transduction pathway in the cells. PMID:7483844

  17. Designing a SCADA system simulator for fast breeder reactor

    NASA Astrophysics Data System (ADS)

    Nugraha, E.; Abdullah, A. G.; Hakim, D. L.

    2016-04-01

    SCADA (Supervisory Control and Data Acquisition) system simulator is a Human Machine Interface-based software that is able to visualize the process of a plant. This study describes the results of the process of designing a SCADA system simulator that aims to facilitate the operator in monitoring, controlling, handling the alarm, accessing historical data and historical trend in Nuclear Power Plant (NPP) type Fast Breeder Reactor (FBR). This research used simulation to simulate NPP type FBR Kalpakkam in India. This simulator was developed using Wonderware Intouch software 10 and is equipped with main menu, plant overview, area graphics, control display, set point display, alarm system, real-time trending, historical trending and security system. This simulator can properly simulate the principle of energy flow and energy conversion process on NPP type FBR. This SCADA system simulator can be used as training media for NPP type FBR prospective operators.

  18. Modeling and Simulation for Mission Operations Work System Design

    NASA Technical Reports Server (NTRS)

    Sierhuis, Maarten; Clancey, William J.; Seah, Chin; Trimble, Jay P.; Sims, Michael H.

    2003-01-01

    Work System analysis and design is complex and non-deterministic. In this paper we describe Brahms, a multiagent modeling and simulation environment for designing complex interactions in human-machine systems. Brahms was originally conceived as a business process design tool that simulates work practices, including social systems of work. We describe our modeling and simulation method for mission operations work systems design, based on a research case study in which we used Brahms to design mission operations for a proposed discovery mission to the Moon. We then describe the results of an actual method application project-the Brahms Mars Exploration Rover. Space mission operations are similar to operations of traditional organizations; we show that the application of Brahms for space mission operations design is relevant and transferable to other types of business processes in organizations.

  19. Simulation in the Service of Design - Asking the Right Questions

    SciTech Connect

    Donn, Michael; Selkowitz, Stephen; Bordass, Bill

    2009-03-01

    This paper proposes an approach to the creation of design tools that address the real information needs of designers in the early stages of design of nonresidential buildings. Traditional simplified design tools are typically too limited to be of much use, even in conceptual design. The proposal is to provide access to the power of detailed simulation tools, at a stage in design when little is known about the final building, but at a stage also when the freedom to explore options is greatest. The proposed approach to tool design has been derived from consultation with design analysis teams as part of the COMFEN tool development. The paper explores how tools like COMFEN have been shaped by this consultation and how requests from these teams for real-world relevance might shape such tools in the future, drawing into the simulation process the lessons from Post Occupancy Evaluation (POE) of buildings.

  20. Design and simulation of an ultrasonic transducer

    NASA Astrophysics Data System (ADS)

    Yu, Zhenxian; Shi, Yanru; Hsu, Hung-Yao; Kong, Lingxue

    2005-12-01

    This paper presents a novel ultrasonic transducer which can be used as a liquid ejector to release drug. The ultrasonic transducer is based on the design of a flextensional transducer, which is composed of interdigital piezoelectric rings and a vibration membrane. The device works at an axisymmetric resonant mode to produce maximum amplitude at the center of the vibration membrane in axial direction. For the usage of multi piezoelectric rings, the flexural plate waves can be generated by applying two out-of-phase signals. The power consumption is of primary importance in the design of this device and the usage of single-ring or multi-ring piezoelectric material instead of bulk piezo material can therefore reduce the power consumption. An optimum working frequency, at which least power is required by the device, can be found by the piezoelectric, coupled field capability of the ANSYS/Multiphysics product.

  1. Arrow 227: Air transport system design simulation

    NASA Technical Reports Server (NTRS)

    Bontempi, Michael; Bose, Dave; Brophy, Georgeann; Cashin, Timothy; Kanarios, Michael; Ryan, Steve; Peterson, Timothy

    1992-01-01

    The Arrow 227 is a student-designed commercial transport for use in a overnight package delivery network. The major goal of the concept was to provide the delivery service with the greatest potential return on investment. The design objectives of the Arrow 227 were based on three parameters; production cost, payload weight, and aerodynamic efficiency. Low production cost helps to reduce initial investment. Increased payload weight allows for a decrease in flight cycles and, therefore, less fuel consumption than an aircraft carrying less payload weight and requiring more flight cycles. In addition, fewer flight cycles will allow a fleet to last longer. Finally, increased aerodynamic efficiency in the form of high L/D will decrease fuel consumption.

  2. Design of object-oriented distributed simulation classes

    NASA Technical Reports Server (NTRS)

    Schoeffler, James D. (Principal Investigator)

    1995-01-01

    Distributed simulation of aircraft engines as part of a computer aided design package is being developed by NASA Lewis Research Center for the aircraft industry. The project is called NPSS, an acronym for 'Numerical Propulsion Simulation System'. NPSS is a flexible object-oriented simulation of aircraft engines requiring high computing speed. It is desirable to run the simulation on a distributed computer system with multiple processors executing portions of the simulation in parallel. The purpose of this research was to investigate object-oriented structures such that individual objects could be distributed. The set of classes used in the simulation must be designed to facilitate parallel computation. Since the portions of the simulation carried out in parallel are not independent of one another, there is the need for communication among the parallel executing processors which in turn implies need for their synchronization. Communication and synchronization can lead to decreased throughput as parallel processors wait for data or synchronization signals from other processors. As a result of this research, the following have been accomplished. The design and implementation of a set of simulation classes which result in a distributed simulation control program have been completed. The design is based upon MIT 'Actor' model of a concurrent object and uses 'connectors' to structure dynamic connections between simulation components. Connectors may be dynamically created according to the distribution of objects among machines at execution time without any programming changes. Measurements of the basic performance have been carried out with the result that communication overhead of the distributed design is swamped by the computation time of modules unless modules have very short execution times per iteration or time step. An analytical performance model based upon queuing network theory has been designed and implemented. Its application to realistic configurations has

  3. Design of Object-Oriented Distributed Simulation Classes

    NASA Technical Reports Server (NTRS)

    Schoeffler, James D.

    1995-01-01

    Distributed simulation of aircraft engines as part of a computer aided design package being developed by NASA Lewis Research Center for the aircraft industry. The project is called NPSS, an acronym for "Numerical Propulsion Simulation System". NPSS is a flexible object-oriented simulation of aircraft engines requiring high computing speed. It is desirable to run the simulation on a distributed computer system with multiple processors executing portions of the simulation in parallel. The purpose of this research was to investigate object-oriented structures such that individual objects could be distributed. The set of classes used in the simulation must be designed to facilitate parallel computation. Since the portions of the simulation carried out in parallel are not independent of one another, there is the need for communication among the parallel executing processors which in turn implies need for their synchronization. Communication and synchronization can lead to decreased throughput as parallel processors wait for data or synchronization signals from other processors. As a result of this research, the following have been accomplished. The design and implementation of a set of simulation classes which result in a distributed simulation control program have been completed. The design is based upon MIT "Actor" model of a concurrent object and uses "connectors" to structure dynamic connections between simulation components. Connectors may be dynamically created according to the distribution of objects among machines at execution time without any programming changes. Measurements of the basic performance have been carried out with the result that communication overhead of the distributed design is swamped by the computation time of modules unless modules have very short execution times per iteration or time step. An analytical performance model based upon queuing network theory has been designed and implemented. Its application to realistic configurations has not

  4. NAM: The 2004 RAS National Astronomy Meeting

    NASA Astrophysics Data System (ADS)

    Jones, Barrie; Norton, Andrew

    2004-06-01

    This year's RAS National Astronomy Meeting was held at the Open University's Milton Keynes campus from 29 March to 2 April. The event was organized by members of the OU Physics & Astronomy Department and Planetary & Space Science Research Institute. Around 450 people attended the meeting, at which more than 220 talks were presented, along with around 90 posters. Co-chairs of RAS NAM04, Barrie Jones and Andrew Norton, summarize.

  5. Hypervelocity impact simulation for micrometeorite and debris shield design

    NASA Technical Reports Server (NTRS)

    Fahrenthold, Eric P.

    1992-01-01

    A new capability has been developed for direct computer simulation of hypervelocity impacts on multi-plate orbital debris shields, for combinations of low shield thickness and wide shield spacing which place extreme demands on conventional Eulerian analysis techniques. The modeling methodology represents a novel approach to debris cloud dynamics simulation, a problem of long term interest in the design of space structures. Software implementation of the modeling methodology provides a new design tool for engineering analysis of proposed orbital debris protection systems.

  6. Design Model for Learner-Centered, Computer-Based Simulations.

    ERIC Educational Resources Information Center

    Hawley, Chandra L.; Duffy, Thomas M.

    This paper presents a model for designing computer-based simulation environments within a constructivist framework for the K-12 school setting. The following primary criteria for the development of simulations are proposed: (1) the problem needs to be authentic; (2) the cognitive demand in learning should be authentic; (3) scaffolding supports a…

  7. The Design, Development, and Evaluation of an Evaluative Computer Simulation.

    ERIC Educational Resources Information Center

    Ehrlich, Lisa R.

    This paper discusses evaluation design considerations for a computer based evaluation simulation developed at the University of Iowa College of Medicine in Cardiology to assess the diagnostic skills of primary care physicians and medical students. The simulation developed allows for the assessment of diagnostic skills of physicians in the…

  8. Inhibition of RAS in diabetic nephropathy

    PubMed Central

    Yacoub, Rabi; Campbell, Kirk N

    2015-01-01

    Diabetic kidney disease (DKD) is a progressive proteinuric renal disorder in patients with type 1 or type 2 diabetes mellitus. It is a common cause of end-stage kidney disease worldwide, particularly in developed countries. Therapeutic targeting of the renin–angiotensin system (RAS) is the most validated clinical strategy for slowing disease progression. DKD is paradoxically a low systematic renin state with an increased intrarenal RAS activity implicated in its pathogenesis. Angiotensin II (AngII), the main peptide of RAS, is not only a vasoactive peptide but functions as a growth factor, activating interstitial fibroblasts and mesangial and tubular cells, while promoting the synthesis of extracellular matrix proteins. AngII also promotes podocyte injury through increased calcium influx and the generation of reactive oxygen species. Blockade of the RAS using either angiotensin converting enzyme inhibitors, or angiotensin receptor blockers can attenuate progressive glomerulosclerosis in animal models, and slows disease progression in humans with DKD. In this review, we summarize the role of intrarenal RAS activation in the pathogenesis and progression of DKD and the rationale for RAS inhibition in this population. PMID:25926752

  9. Effectively design and simulate thermosyphon reboiler systems. Part 1

    SciTech Connect

    Martin, G.R.; Sloley, A.W.

    1995-06-01

    Thermosyphon reboilers provide a simple, low-maintenance design for distillation tower reboiler systems. With an understanding of all the factors involved, thermosyphon designs should be more reliable than most other reboiler systems due to an absence of moving parts (pumps) in the process circulation loop. Design of true thermosyphon exchangers requires an intimate knowledge of a distillation tower`s heat balance, temperature levels and pressure balance in there boiler loop. Temperature levels vary strongly with composition gradients depending on the system relative volatilities. Case studies of two industrial units demonstrate implications on exchanger design of the correct and incorrect simulation configuration. The two cases compare a low relative-volatility {alpha} system (ethylene-ethane splitter) and a high {alpha} system (FCCU deethanizer). Main factors include impact on equipment size and design. Proper design criteria for thermosyphon exchanger and distillation tower simulation and for integrating process and equipment design are also shown.

  10. ASPP1 and ASPP2 bind active RAS, potentiate RAS signalling and enhance p53 activity in cancer cells

    PubMed Central

    Wang, Y; Godin-Heymann, N; Dan Wang, X; Bergamaschi, D; Llanos, S; Lu, X

    2013-01-01

    RAS mutations occur frequently in human cancer and activated RAS signalling contributes to tumour development and progression. Apart from its oncogenic effects on cell growth, active RAS has tumour-suppressive functions via its ability to induce cellular senescence and apoptosis. RAS is known to induce p53-dependent cell cycle arrest, yet its effect on p53-dependent apoptosis remains unclear. We report here that apoptosis-stimulating protein of p53 (ASPP) 1 and 2, two activators of p53, preferentially bind active RAS via their N-terminal RAS-association domains (RAD). Additionally, ASPP2 colocalises with and contributes to RAS cellular membrane localisation and potentiates RAS signalling. In cancer cells, ASPP1 and ASPP2 cooperate with oncogenic RAS to enhance the transcription and apoptotic function of p53. Thus, loss of ASPP1 and ASPP2 in human cancer cells may contribute to the full transforming property of RAS oncogene. PMID:23392125

  11. Design Factors for Educationally Effective Animations and Simulations

    ERIC Educational Resources Information Center

    Plass, Jan L.; Homer, Bruce D.; Hayward, Elizabeth O.

    2009-01-01

    This paper reviews research on learning from dynamic visual representations and offers principles for the design of animations and simulations that assure their educational effectiveness. In addition to established principles, new and revised design principle are presented that have been derived from recent research. Our review focuses on the…

  12. Simulations Using a Computer/Videodisc System: Instructional Design Considerations.

    ERIC Educational Resources Information Center

    Ehrlich, Lisa R.

    Instructional design considerations involved in using level four videodisc systems when designing simulations are explored. Discussion of the hardware and software system characteristics notes that computer based training offers the features of text, graphics, color, animation, and highlighting techniques, while a videodisc player offers all of…

  13. Advanced Simulation and Computing Co-Design Strategy

    SciTech Connect

    Ang, James A.; Hoang, Thuc T.; Kelly, Suzanne M.; McPherson, Allen; Neely, Rob

    2015-11-01

    This ASC Co-design Strategy lays out the full continuum and components of the co-design process, based on what we have experienced thus far and what we wish to do more in the future to meet the program’s mission of providing high performance computing (HPC) and simulation capabilities for NNSA to carry out its stockpile stewardship responsibility.

  14. Design by Dragging: An Interface for Creative Forward and Inverse Design with Simulation Ensembles

    PubMed Central

    Coffey, Dane; Lin, Chi-Lun; Erdman, Arthur G.; Keefe, Daniel F.

    2014-01-01

    We present an interface for exploring large design spaces as encountered in simulation-based engineering, design of visual effects, and other tasks that require tuning parameters of computationally-intensive simulations and visually evaluating results. The goal is to enable a style of design with simulations that feels as-direct-as-possible so users can concentrate on creative design tasks. The approach integrates forward design via direct manipulation of simulation inputs (e.g., geometric properties, applied forces) in the same visual space with inverse design via “tugging” and reshaping simulation outputs (e.g., scalar fields from finite element analysis (FEA) or computational fluid dynamics (CFD)). The interface includes algorithms for interpreting the intent of users’ drag operations relative to parameterized models, morphing arbitrary scalar fields output from FEA and CFD simulations, and in-place interactive ensemble visualization. The inverse design strategy can be extended to use multi-touch input in combination with an as-rigid-as-possible shape manipulation to support rich visual queries. The potential of this new design approach is confirmed via two applications: medical device engineering of a vacuum-assisted biopsy device and visual effects design using a physically based flame simulation. PMID:24051845

  15. Mapping the functional versatility and fragility of Ras GTPase signaling circuits through in vitro network reconstitution

    PubMed Central

    Coyle, Scott M; Lim, Wendell A

    2016-01-01

    The Ras-superfamily GTPases are central controllers of cell proliferation and morphology. Ras signaling is mediated by a system of interacting molecules: upstream enzymes (GEF/GAP) regulate Ras’s ability to recruit multiple competing downstream effectors. We developed a multiplexed, multi-turnover assay for measuring the dynamic signaling behavior of in vitro reconstituted H-Ras signaling systems. By including both upstream regulators and downstream effectors, we can systematically map how different network configurations shape the dynamic system response. The concentration and identity of both upstream and downstream signaling components strongly impacted the timing, duration, shape, and amplitude of effector outputs. The distorted output of oncogenic alleles of Ras was highly dependent on the balance of positive (GAP) and negative (GEF) regulators in the system. We found that different effectors interpreted the same inputs with distinct output dynamics, enabling a Ras system to encode multiple unique temporal outputs in response to a single input. We also found that different Ras-to-GEF positive feedback mechanisms could reshape output dynamics in distinct ways, such as signal amplification or overshoot minimization. Mapping of the space of output behaviors accessible to Ras provides a design manual for programming Ras circuits, and reveals how these systems are readily adapted to produce an array of dynamic signaling behaviors. Nonetheless, this versatility comes with a trade-off of fragility, as there exist numerous paths to altered signaling behaviors that could cause disease. DOI: http://dx.doi.org/10.7554/eLife.12435.001 PMID:26765565

  16. Binding hotspots on K-Ras: consensus ligand binding sites and other reactive regions from probe-based molecular dynamics analysis

    PubMed Central

    Prakash, Priyanka; Hancock, John F.; Gorfe, Alemayehu A.

    2015-01-01

    We have used probe-based molecular dynamics (pMD) simulations to search for interaction hotspots on the surface of the therapeutically highly relevant oncogenic K-Ras G12D. Combining the probe-based query with an ensemble-based pocket identification scheme and an analysis of existing Ras-ligand complexes, we show that (i) pMD is a robust and cost-effective strategy for binding site identification, (ii) all four of the previously reported ligand binding sites are suitable for structure-based ligand design, and (iii) in some cases probe binding and expanded sampling of configurational space enable pocket expansion and increase the likelihood of site identification. Furthermore, by comparing the distribution of hotspots in non-pocket-like regions with known protein- and membrane-interacting interfaces, we propose that pMD has the potential to predict surface patches responsible for protein-biomolecule interactions. These observations have important implications for future drug design efforts and will facilitate the search for potential interfaces responsible for the proposed transient oligomerization or interaction of Ras with other biomolecules in the cellular milieu. PMID:25740554

  17. Evolutionary Design and Simulation of a Tube Crawling Inspection Robot

    NASA Technical Reports Server (NTRS)

    Craft, Michael; Howsman, Tom; ONeil, Daniel; Howell, Joe T. (Technical Monitor)

    2002-01-01

    The Space Robotics Assembly Team Simulation (SpaceRATS) is an expansive concept that will hopefully lead to a space flight demonstration of a robotic team cooperatively assembling a system from its constitutive parts. A primary objective of the SpaceRATS project is to develop a generalized evolutionary design approach for multiple classes of robots. The portion of the overall SpaceRats program associated with the evolutionary design and simulation of an inspection robot's morphology is the subject of this paper. The vast majority of this effort has concentrated on the use and modification of Darwin2K, a robotic design and simulation software package, to analyze the design of a tube crawling robot. This robot is designed for carrying out inspection duties in relatively inaccessible locations within a liquid rocket engine similar to the SSME. A preliminary design of the tube crawler robot was completed, and the mechanical dynamics of the system were simulated. An evolutionary approach to optimizing a few parameters of the system was utilized, resulting in a more optimum design.

  18. Activated K-Ras, But Not H-Ras or N-Ras, Regulates Brain Neural Stem Cell Proliferation in a Raf/Rb-Dependent Manner

    PubMed Central

    Bender, R. Hugh F.; Haigis, Kevin M.; Gutmann, David H.

    2016-01-01

    Neural stem cells (NSCs) give rise to all the major cell types in the brain, including neurons, oligodendrocytes, and astrocytes. However, the intracellular signaling pathways that govern brain NSC proliferation and differentiation have been incompletely characterized to date. Since some neurodevelopmental brain disorders (Costello syndrome and Noonan syndrome) are caused by germline activating mutations in the RAS genes, Ras small GTPases are likely critical regulators of brain NSC function. In the mammalian brain, Ras exists as three distinct molecules (H-Ras, K-Ras, and N-Ras), each with different subcellular localizations, downstream signaling effectors, and biological effects. Leveraging a novel series of conditional-activated Ras molecule-expressing genetically engineered mouse strains, we demonstrate that activated K-Ras, but not H-Ras or N-Ras, expression increases brain NSC growth in a Raf-dependent, but Mek-independent, manner. Moreover, we show that activated K-Ras regulation of brain NSC proliferation requires Raf binding and suppression of retinoblastoma (Rb) function. Collectively, these observations establish tissue-specific differences in activated Ras molecule regulation of brain cell growth that operate through a noncanonical mechanism. PMID:25788415

  19. Past, Present, and Future of Targeting Ras for Cancer Therapies.

    PubMed

    Tan, Zhi; Zhang, Shuxing

    2016-01-01

    For decades, mutant Ras (mut-Ras) proteins have been identified as drivers of multiple cancers including pancreatic, lung, and colon cancers. However, targeting this oncogene has been challenging and no Ras inhibitors are on the market to date. Lately several candidates targeting the downstream pathways of Ras signaling, including PI3K and Raf, were approved for cancer treatment. However, they do not present promising therapeutic effects on patients harboring Ras mutations. Recently, a variety of compounds have been reported to impair the activity of Ras, and these exciting discoveries reignite the hope for development of novel drugs targeting mut-Ras. In this article, we will review the progress made in this field and the current state-of-the-art technologies to develop Ras inhibitors. Also we will discuss the future direction of targeting Ras. PMID:26423695

  20. RasGRP1 and RasGRP3 Are Required for Efficient Generation of Early Thymic Progenitors.

    PubMed

    Golec, Dominic P; Henao Caviedes, Laura M; Baldwin, Troy A

    2016-09-01

    T cell development is dependent on the migration of progenitor cells from the bone marrow to the thymus. Upon reaching the thymus, progenitors undergo a complex developmental program that requires inputs from various highly conserved signaling pathways including the Notch and Wnt pathways. To date, Ras signaling has not been implicated in the very earliest stages of T cell differentiation, but members of a family of Ras activators called RasGRPs have been shown to be involved at multiple stages of T cell development. We examined early T cell development in mice lacking RasGRP1, RasGRP3, and RasGRPs 1 and 3. We report that RasGRP1- and RasGRP3-deficient thymi show significantly reduced numbers of early thymic progenitors (ETPs) relative to wild type thymi. Furthermore, RasGRP1/3 double-deficient thymi show significant reductions in ETP numbers compared with either RasGRP1 or RasGRP3 single-deficient thymi, suggesting that both RasGRP1 and RasGRP3 regulate the generation of ETPs. In addition, competitive bone marrow chimera experiments reveal that RasGRP1/3 double-deficient progenitors intrinsically generate ETPs less efficiently than wild type progenitors. Finally, RasGRP1/3-deficient progenitors show impaired migration toward the CCR9 ligand, CCL25, suggesting that RasGRP1 and RasGRP3 may regulate progenitor entry into the thymus through a CCR9-dependent mechanism. These data demonstrate that, in addition to Notch and Wnt, the highly conserved Ras pathway is critical for the earliest stages of T cell development and further highlight the importance of Ras signaling during thymocyte maturation. PMID:27465532

  1. Design, simulation, evaluation, and technological verification of arrayed waveguide gratings

    NASA Astrophysics Data System (ADS)

    Seyringer, Dana; Schmid, Patrick; Bielik, Michal; Uherek, Frantisek; Chovan, Jozef; Kuzma, Anton

    2014-07-01

    We present the design, simulation, evaluation, and technological verification of various low-index optical demultiplexers based on arrayed waveguide gratings (AWGs). When designing such optical demultiplexers, a set of input geometrical parameters must be first calculated. They are essential to create AWG layout that will be then simulated using commercial photonics tools. However, these tools do not support or support only partially such a fundamental calculation. Therefore, a new stand-alone tool called AWG-Parameters was developed, which strongly reduces the time needed for the design. From the calculated geometrical parameters, the AWG layouts were created and simulated using three commercial photonic tools: Optiwave, (Ottawa, Ontario, Canada), Apollo Photonics, (Ancaster, Ontario, Canada), and R-Soft, (Pasadena, California). The designs were also technologically verified. The simulated/measured transmission characteristics were evaluated by our newly developed AWG-Analyzer tool. This tool provides calculations of AWG transmission parameters, which are also missing in commercial photonic tools. Additionally, the tool provides clear definitions of calculated transmission parameters together with their textual and graphical representations. Finally, the transmission characteristics and parameters achieved from different photonic tools were compared with each other and discussed in detail. The simulated results were also compared with the measurements. Very good agreement was achieved between theoretical (AWG-Parameters tool), simulated (commercial photonic tools), and fabricated AWG transmission parameters.

  2. Ras Conformational Ensembles, Allostery, and Signaling.

    PubMed

    Lu, Shaoyong; Jang, Hyunbum; Muratcioglu, Serena; Gursoy, Attila; Keskin, Ozlem; Nussinov, Ruth; Zhang, Jian

    2016-06-01

    Ras proteins are classical members of small GTPases that function as molecular switches by alternating between inactive GDP-bound and active GTP-bound states. Ras activation is regulated by guanine nucleotide exchange factors that catalyze the exchange of GDP by GTP, and inactivation is terminated by GTPase-activating proteins that accelerate the intrinsic GTP hydrolysis rate by orders of magnitude. In this review, we focus on data that have accumulated over the past few years pertaining to the conformational ensembles and the allosteric regulation of Ras proteins and their interpretation from our conformational landscape standpoint. The Ras ensemble embodies all states, including the ligand-bound conformations, the activated (or inactivated) allosteric modulated states, post-translationally modified states, mutational states, transition states, and nonfunctional states serving as a reservoir for emerging functions. The ensemble is shifted by distinct mutational events, cofactors, post-translational modifications, and different membrane compositions. A better understanding of Ras biology can contribute to therapeutic strategies. PMID:26815308

  3. Biologically-inspired hexapod robot design and simulation

    NASA Technical Reports Server (NTRS)

    Espenschied, Kenneth S.; Quinn, Roger D.

    1994-01-01

    The design and construction of a biologically-inspired hexapod robot is presented. A previously developed simulation is modified to include models of the DC drive motors, the motor driver circuits and their transmissions. The application of this simulation to the design and development of the robot is discussed. The mechanisms thought to be responsible for the leg coordination of the walking stick insect were previously applied to control the straight-line locomotion of a robot. We generalized these rules for a robot walking on a plane. This biologically-inspired control strategy is used to control the robot in simulation. Numerical results show that the general body motion and performance of the simulated robot is similar to that of the robot based on our preliminary experimental results.

  4. Vestibular models for design and evaluation of flight simulator motion

    NASA Technical Reports Server (NTRS)

    Bussolari, S. R.; Sullivan, R. B.; Young, L. R.

    1986-01-01

    The use of spatial orientation models in the design and evaluation of control systems for motion-base flight simulators is investigated experimentally. The development of a high-fidelity motion drive controller using an optimal control approach based on human vestibular models is described. The formulation and implementation of the optimal washout system are discussed. The effectiveness of the motion washout system was evaluated by studying the response of six motion washout systems to the NASA/AMES Vertical Motion Simulator for a single dash-quick-stop maneuver. The effects of the motion washout system on pilot performance and simulator acceptability are examined. The data reveal that human spatial orientation models are useful for the design and evaluation of flight simulator motion fidelity.

  5. RasGRP3, a Ras activator, contributes to signaling and the tumorigenic phenotype in human melanoma

    PubMed Central

    Li, Luowei; Kedei, Noemi; Tóth, Zsuzsanna E.; Czap, Alexandra; Velasquez, Julia F.; Mihova, Daniela; Michalowski, Aleksandra M.; Yuspa, Stuart H.; Blumberg, Peter M.

    2014-01-01

    RasGRP3, an activator for H-Ras, R-Ras and Rap1/2, has emerged as an important mediator of signaling downstream from receptor coupled phosphoinositide turnover in B and T cells. Here, we report that RasGRP3 showed a high level of expression in multiple human melanoma cell lines as well as in a subset of human melanoma tissue samples. Suppression of endogenous RasGRP3 expression in these melanoma cell lines reduced Ras-GTP formation as well as c-Met expression and Akt phosphorylation downstream from HGF or EGF stimulation. RasGRP3 suppression also inhibited cell proliferation and reduced both colony formation in soft agar and xenograft tumor growth in immunodeficient mice, demonstrating the importance of RasGRP3 for the transformed phenotype of the melanoma cells. Reciprocally, overexpression of RasGRP3 in human primary melanocytes altered cellular morphology, markedly enhanced cell proliferation, and rendered the cells tumorigenic in a mouse xenograft model. Suppression of RasGRP3 expression in these cells inhibited downstream RasGRP3 responses and suppressed cell growth, confirming the functional role of RasGRP3 in the altered behavior of these cells. The identification of the role of RasGRP3 in melanoma highlights its importance, as a Ras activator, in the phosphoinositide signaling pathway in human melanoma and provides a new potential therapeutic target. PMID:21602881

  6. Basal but not luminal mammary epithelial cells require PI3K/mTOR signaling for Ras-driven overgrowth.

    PubMed

    Plichta, Kristin A; Mathers, Jessica L; Gestl, Shelley A; Glick, Adam B; Gunther, Edward J

    2012-11-15

    The mammary ducts of humans and mice are comprised of two main mammary epithelial cell (MEC) subtypes: a surrounding layer of basal MECs and an inner layer of luminal MECs. Breast cancer subtypes show divergent clinical behavior that may reflect properties inherent in their MEC compartment of origin. How the response to a cancer-initiating genetic event is shaped by MEC subtype remains largely unexplored. Using the mouse mammary gland, we designed organotypic three-dimensional culture models that permit challenge of discrete MEC compartments with the same oncogenic insult. Mammary organoids were prepared from mice engineered for compartment-restricted coexpression of oncogenic H-RAS(G12V) together with a nuclear fluorescent reporter. Monitoring of H-RAS(G12V)-expressing MECs during extended live cell imaging permitted visualization of Ras-driven phenotypes via video microscopy. Challenging either basal or luminal MECs with H-RAS(G12V) drove MEC proliferation and survival, culminating in aberrant organoid overgrowth. In each compartment, Ras activation triggered modes of collective MEC migration and invasion that contrasted with physiologic modes used during growth factor-initiated branching morphogenesis. Although basal and luminal Ras activation produced similar overgrowth phenotypes, inhibitor studies revealed divergent use of Ras effector pathways. Blocking either the phosphoinositide 3-kinase or the mammalian target of rapamycin pathway completely suppressed Ras-driven invasion and overgrowth of basal MECs, but only modestly attenuated Ras-driven phenotypes in luminal MECs. We show that MEC subtype defines signaling pathway dependencies downstream of Ras. Thus, cells-of-origin may critically determine the drug sensitivity profiles of mammary neoplasia. PMID:23010075

  7. Specific repression of mutant K-RAS by 10-23 DNAzyme: Sensitizing cancer cell to anti-cancer therapies

    SciTech Connect

    Yu, S.-H.; Wang, T.-H.; Au, L.-C.

    2009-01-09

    Point mutations of the Ras family are frequently found in human cancers at a prevalence rate of 30%. The most common mutation K-Ras(G12V), required for tumor proliferation, survival, and metastasis due to its constitutively active GTPase activity, has provided an ideal target for cancer therapy. 10-23 DNAzyme, an oligodeoxyribonucleotide-based ribonuclease consisting of a 15-nucleotide catalytical domain flanked by two target-specific complementary arms, has been shown to effectively cleave the target mRNA at purine-pyrimidine dinucleotide. Taking advantage of this specific property, 10-23 DNAzyme was designed to cleave mRNA of K-Ras(G12V)(GGU {yields} GUU) at the GU dinucleotide while left the wild-type (WT) K-Ras mRNA intact. The K-Ras(G12V)-specific 10-23 DNAzyme was able to reduce K-Ras(G12V) at both mRNA and protein levels in SW480 cell carrying homozygous K-Ras(G12V). No effect was observed on the WT K-Ras in HEK cells. Although K-Ras(G12V)-specific DNAzymes alone did not inhibit proliferation of SW480 or HEK cells, pre-treatment of this DNAzyme sensitized the K-Ras(G12V) mutant cells to anti-cancer agents such as doxorubicin and radiation. These results offer a potential of using allele-specific 10-23 DNAzyme in combination with other cancer therapies to achieve better effectiveness on cancer treatment.

  8. LEGO - A Class Library for Accelerator Design and Simulation

    SciTech Connect

    Cai, Yunhai

    1998-11-19

    An object-oriented class library of accelerator design and simulation is designed and implemented in a simple and modular fashion. All physics of single-particle dynamics is implemented based on the Hamiltonian in the local frame of the component. Symplectic integrators are used to approximate the integration of the Hamiltonian. A differential algebra class is introduced to extract a Taylor map up to arbitrary order. Analysis of optics is done in the same way both for the linear and non-linear cases. Recently, Monte Carlo simulation of synchrotron radiation has been added into the library. The code is used to design and simulate the lattices of the PEP-II and SPEAR3. And it is also used for the commissioning of the PEP-II. Some examples of how to use the library will be given.

  9. Simulation system architecture design for generic communications link

    NASA Technical Reports Server (NTRS)

    Tsang, Chit-Sang; Ratliff, Jim

    1986-01-01

    This paper addresses a computer simulation system architecture design for generic digital communications systems. It addresses the issues of an overall system architecture in order to achieve a user-friendly, efficient, and yet easily implementable simulation system. The system block diagram and its individual functional components are described in detail. Software implementation is discussed with the VAX/VMS operating system used as a target environment.

  10. New tools for the simulation and design of calorimeters

    SciTech Connect

    Womersley, W.J.

    1989-07-10

    Two new approaches to the simulation and design of large hermetic calorimeters are presented. Firstly, the Shower Library scheme used in the fast generation of showers in the Monte Carlo of the calorimeter for the D-Zero experiment at the Fermilab Tevatron is described. Secondly, a tool for the design future calorimeters is described, which can be integrated with a computer aided design system to give engineering designers an immediate idea of the relative physics capabilities of different geometries. 9 refs., 6 figs., 1 tab.

  11. Designing and implementing full immersion simulation as a research tool.

    PubMed

    Munroe, Belinda; Buckley, Thomas; Curtis, Kate; Morris, Richard

    2016-05-01

    Simulation is a valuable research tool used to evaluate the clinical performance of devices, people and systems. The simulated setting may address concerns unique to complex clinical environments such as the Emergency Department, which make the conduct of research challenging. There is limited evidence available to inform the development of simulated clinical scenarios for the purpose of evaluating practice in research studies, with the majority of literature focused on designing simulated clinical scenarios for education and training. Distinct differences exist in scenario design when implemented in education compared with use in clinical research studies. Simulated scenarios used to assess practice in clinical research must not comprise of any purposeful or planned teaching and be developed with a high degree of validity and reliability. A new scenario design template was devised to develop two standardised simulated clinical scenarios for the evaluation of a new assessment framework for emergency nurses. The scenario development and validation processes undertaken are described and provide an evidence-informed guide to scenario development for future clinical research studies. PMID:26917415

  12. Software Design for Interactive Graphic Radiation Treatment Simulation Systems*

    PubMed Central

    Kalet, Ira J.; Sweeney, Christine; Jacky, Jonathan

    1990-01-01

    We examine issues in the design of interactive computer graphic simulation programs for radiation treatment planning (RTP), as well as expert system programs that automate parts of the RTP process, in light of ten years of experience at designing, building and using such programs. An experiment in object-oriented design using standard Pascal shows that while some advantage is gained from the design, it is still difficult to achieve modularity and to integrate expert system components. A new design based on the Common LISP Object System (CLOS) is described. This series of designs for RTP software shows that this application benefits in specific ways from object-oriented design methods and appropriate languages and tools.

  13. Using simulation to design a central sterilization department.

    PubMed

    Lin, Feng; Lawley, Mark; Spry, Charlie; McCarthy, Kelly; Coyle-Rogers, Patricia G; Yih, Yuehwern

    2008-10-01

    A simulation project was performed to assist with redesign of the surgery department of a large tertiary hospital and to help administrators make the best decisions about relocating, staffing, and equipping the central sterilization department. A simulation model was created to analyze department configurations, staff schedules, equipment capacities, and cart-washing requirements. Performance measures examined include tray turnaround time, surgery-delay rate, and work-in-process levels. The analysis provides significant insight into how the proposed system will perform, allowing planning for expected patient volume increases. This work illustrates how simulation can facilitate the design of a central sterilization department and improve surgical sterilization operations. PMID:18928959

  14. An Integrated Approach for Entry Mission Design and Flight Simulations

    NASA Technical Reports Server (NTRS)

    Lu, Ping; Rao, Prabhakara

    2004-01-01

    An integrated approach for entry trajectory design, guidance, and simulation is proposed. The key ingredients for this approach are an on-line 3 degree-of-freedom entry trajectory planning algorithm and the entry guidance algorithm that generates the guidance gains automatically. When fully developed, such a tool could enable end-bend entry mission design and simulations in 3DOF and 6DOF mode from de-orbit burn to the TAEM interface and beyond, all in one key stroke. Some preliminary examples of such a capability are presented in this paper that demonstrate the potential of this type of integrated environment.

  15. SCALED SIMULATION DESIGN OF HIGH QUALITY LASER WAKEFIELD ACCELERATOR STAGES

    SciTech Connect

    Geddes, C.G.R.; Cormier-Michel, E.; Esarey, E.; Schroeder, C.B.; Leemans, W.P.; Bruhwiler, D.L.; Cowan, B.; Nieter, C.; Paul, K.; Cary, J.R.

    2009-05-04

    Design of efficient, high gradient laser driven wakefield accelerator (LWFA) stages using explicit particle-incell simulations with physical parameters scaled by plasma density is presented. LWFAs produce few percent energy spread electron bunches at 0.1-1 GeV with high accelerating gradients. Design tools are now required to predict and improve performance and efficiency of future LWFA stages. Scaling physical parameters extends the reach of explicit simulations to address applications including 10 GeV stages and stages for radiation sources, and accurately resolves deep laser depletion to evaluate efficient stages.

  16. MLS, a magnetic logic simulator for magnetic bubble logic design

    NASA Astrophysics Data System (ADS)

    Kinsman, Thomas B.; Cendes, Zoltan J.

    1987-04-01

    A computer program that simulates the logic functions of magnetic bubble devices has been developed. The program uses a color graphics screen to display the locations of bubbles on a chip during operation. It complements the simulator previously developed for modeling bubble devices on the gate level [Smith et al., IEEE Trans. Magn. MAG-19, 1835 (1983); Smith and Kryder, ibid. MAG-21, 1779 (1985)]. This new tool simplifies the design and testing of bubble logic devices, and facilitates the development of complicated LSI bubble circuits. The program operation is demonstrated with the design of an in-stream faulty loop compensator using bubble logic.

  17. Design and simulation challenges for FERMI@elettra

    NASA Astrophysics Data System (ADS)

    Di Mitri, S.; Allaria, E.; Badano, L.; Bontoiu, C.; Cornacchia, M.; Craievich, P.; Danailov, M.; De Ninno, G.; Diviacco, B.; Ferrando, O.; Ferry, S.; Iazzourene, F.; Milton, S. V.; Penco, G.; Spampinati, S.; Trovo', M.; Veronese, M.; Fawley, W.; Lidia, S.; Penn, G.; Qiang, J.; Sonnad, K. G.; Venturini, M.; Warnock, R.; Zholents, A. A.; Pogorelov, I. V.; Borland, M.; Bassi, G.; Ellison, J. A.; Heinemann, K.; Fiorito, R.; Shkvarunets, A.; Tobin, J. C.

    2009-09-01

    FERMI@elettra is a fourth-generation light source user facility under construction at the Elettra Laboratory in Trieste, Italy. The high-quality 1.2 GeV electron beam drives two-seeded Free Electron Lasers (FELs) in the wavelength range 100-10 nm. Wavelength tunability, variable polarization and higher electron beam energies to reach even shorter output wavelengths are also in the machine delivery plan. This paper describes the physics processes that have been modelled to simulate FERMI@elettra and the computer codes used to optimize the machine design. The paper focuses on several design challenges and how these translate into modelling and simulation challenges.

  18. An R package for simulation experiments evaluating clinical trial designs.

    PubMed

    Wang, Yuanyuan; Day, Roger

    2010-01-01

    This paper presents an open-source application for evaluating competing clinical trial (CT) designs using simulations. The S4 system of classes and methods is utilized. Using object-oriented programming provides extensibility through careful, clear interface specification; using R, an open-source widely-used statistical language, makes the application extendible by the people who design CTs: biostatisticians. Four key classes define the specifications of the population models, CT designs, outcome models and evaluation criteria. Five key methods define the interfaces for generating patient baseline characteristics, stopping rule, assigning treatment, generating patient outcomes and calculating the criteria. Documentation of their connections with the user input screens, with the central simulation loop, and with each other faciliates the extensibility. New subclasses and instances of existing classes meeting these interfaces can integrate immediately into the application. To illustrate the application, we evaluate the effect of patient pharmacokinetic heterogeneity on the performance of a common Phase I "3+3" design. PMID:21347151

  19. RAS Symposium Draws Hundreds of Attendees | Poster

    Cancer.gov

    They call themselves “rasologists”: scientists who study the RAS family of genes and the cancers that can arise due to mutations within them. This field of research is at the heart of some sobering numbers. Almost a third of all human cancers, including 95 percent of pancreatic cancers, are driven by mutated RAS genes. The American Cancer Society estimates there were 48,960 new cases of pancreatic cancer in the United States in 2015 and 40,560 deaths from the disease.

  20. Design of a neural network simulator on a transputer array

    NASA Technical Reports Server (NTRS)

    Mcintire, Gary; Villarreal, James; Baffes, Paul; Rua, Monica

    1987-01-01

    A brief summary of neural networks is presented which concentrates on the design constraints imposed. Major design issues are discussed together with analysis methods and the chosen solutions. Although the system will be capable of running on most transputer architectures, it currently is being implemented on a 40-transputer system connected to a toroidal architecture. Predictions show a performance level equivalent to that of a highly optimized simulator running on the SX-2 supercomputer.

  1. Technology, design, simulation, and evaluation for SEP-hardened circuits

    NASA Technical Reports Server (NTRS)

    Adams, J. R.; Allred, D.; Barry, M.; Rudeck, P.; Woodruff, R.; Hoekstra, J.; Gardner, H.

    1991-01-01

    This paper describes the technology, design, simulation, and evaluation for improvement of the Single Event Phenomena (SEP) hardness of gate-array and SRAM cells. Through the use of design and processing techniques, it is possible to achieve an SEP error rate less than 1.0 x 10(exp -10) errors/bit-day for a 9O percent worst-case geosynchronous orbit environment.

  2. Design and validation of a simulator for equine joint injections.

    PubMed

    Fox, Victoria; Sinclair, Charlotte; Bolt, David M; Lowe, John; Weller, Renate

    2013-01-01

    Joint injections are commonly used in equine practice for diagnosis and treatment of joint disorders. Performing joint injections is hence an essential skill for equine practitioners. However, opportunities for veterinary students to practice this skill are often scarce in veterinary curricula. The aim of this study was to design and validate an equine joint injection simulator. We hypothesized that the simulator will enhance student ability and confidence in performing joint injections. The simulator was constructed around an equine forelimb skeleton with soft tissues rebuilt using building foam and rubber bands. An electrical circuit including a buzzer, a battery, wire wool in the joints, and a hypodermic needle at the end of the cable was incorporated. If the students placed the needle into the joint correctly, instant auditory feedback was provided by the buzzer. To validate the simulator, 45 veterinary students were allocated to three groups: cadaver limb, textbook, or simulator. Students' ability to perform joint injections was tested and students' opinions were evaluated with a questionnaire. The proportion of students performing a metacarpophalangeal (MCP) joint injection correctly was significantly higher in the cadaver (93%) and simulator (76%) groups compared to the textbook group (50%). There was no significant difference between groups for performing a distal interphalangeal (DIP) joint injection correctly. Students rated the learning experience with the cadaver and simulator group high and with the textbook group low. The joint injection simulator represents an affordable teaching aid that allows students to repeatedly practice this skill in their own time with immediate feedback. PMID:23709111

  3. Conserved electrostatic fields at the Ras-effector interface measured through vibrational Stark effect spectroscopy explain the difference in tilt angle in the Ras binding domains of Raf and RalGDS.

    PubMed

    Walker, David M; Wang, Ruifei; Webb, Lauren J

    2014-10-01

    Vibrational Stark effect (VSE) spectroscopy was used to measure the electrostatic fields present at the interface of the human guanosine triphosphatase (GTPase) Ras docked with the Ras binding domain (RBD) of the protein kinase Raf. Nine amino acids located on the surface of Raf were selected for labeling with a nitrile vibrational probe. Eight of the probe locations were situated along the interface of Ras and Raf, and one probe was 2 nm away on the opposite side of Raf. Vibrational frequencies of the nine Raf nitrile probes were compared both in the monomeric, solvated protein and when docked with wild-type (WT) Ras to construct a comprehensive VSE map of the Ras-Raf interface. Molecular dynamics (MD) simulations employing an umbrella sampling strategy were used to generate a Boltzmann-weighted ensemble of nitrile positions in both the monomeric and docked complexes to determine the effect that docking has on probe location and orientation and to aid in the interpretation of VSE results. These results were compared to an identical study that was previously conducted on nine nitrile probes on the RBD of Ral guanidine dissociation stimulator (RalGDS) to make comparisons between the docked complexes formed when either of the two effectors bind to WT Ras. This comparison finds that there are three regions of conserved electrostatic fields that are formed upon docking of WT Ras with both downstream effectors. Conservation of this pattern in the docked complex then results in different binding orientations observed in otherwise structurally similar proteins. This work supports an electrostatic cause of the known binding tilt angle between the Ras-Raf and Ras-RalGDS complexes. PMID:25127074

  4. The RAS Problem: Turning Off a Broken Switch

    Cancer.gov

    The RAS gene is commonly mutated in cancer and researchers are working to better understand how to develop drugs that can target the RAS protein, which for many years has been considered to be “undruggable.”

  5. RAS Projects at the NCI Frederick National Lab

    Cancer.gov

    The RAS Initiative involves a number of projects focusing on ways to inhibit the proliferation of cancer cells by mutant RAS proteins. Projects are conducted at the FNLCR hub, with collaboration from the research community nationwide.

  6. Visible Light Communication Physical Layer Design for Jist Simulation

    NASA Astrophysics Data System (ADS)

    Tomaš, Boris

    2014-12-01

    Current advances in computer networking consider using visible light spectrum to encode and decode digital data. This approach is relatively non expensive. However, designing appropriate MAC or any other upper layer protocol for Visible Light Communication (VLC) requires appropriate hardware. This paper proposes and implements such hardware simulation (physical layer) that is compatible with existing network stack.

  7. Simulation, design, and analysis of azeotropic distillation operations

    SciTech Connect

    Bossen, B.S.; Joergensen, S.B.; Gani, R. )

    1993-04-01

    The computational tools needed for simulation, design, and analysis of azeotropic distillation operations are described. These tools include simple methods to identify the existence of binary and ternary azeotropes and to classify ternary mixtures as homogeneous or heterogeneous. The tools also include more complex methods to compute the phase diagram (or a heterogeneous liquid boiling surface), predict liquid-vapor phase equilibrium, and/or predict liquid-liquid-vapor phase equilibrium for simulations of batch and continuous distillation column operations. Important new features of these tools are the incorporation of a fast and efficient method for test of phase stability in simulation of distillation operations, the ability to handle a large range of mixtures (including mixtures with supercritical compounds), and the ability for computations covering wide ranges of temperature and pressure. On the basis of these tools, simple and consistent design algorithms are developed. The applicability of the design algorithms is verified through process simulation and analysis of the predicted behavior and data from the open literature. Conditions are given for examples illustrating (when and how possible distillation boundaries can be crossed) how multiple steady states can be obtained. Finally, the effect of changes in operating on the dynamic behavior of the azeotropic distillation columns and the sensitivity of design to the prediction of phase equilibria are presented.

  8. The design and development of a finger joint simulator.

    PubMed

    Joyce, Thomas J

    2016-05-01

    Artificial finger joints lack the long-term clinical success seen with hip and knee prostheses. In part, this can be explained by the challenges of rheumatoid arthritis, a progressive disease which attacks surrounding tissues as well as the joint itself. Therefore, the natural finger joints' biomechanics are adversely affected, and consequently, this imbalance due to subluxing forces further challenges any prosthesis. Many different designs of finger prosthesis have been offered over a period of greater than 50 years. Most of these designs have failed, and it is likely that many of these failures could have been identified had the prostheses been appropriately tested prior to implantation into patients. While finger joint simulators have been designed, arguably only those from a single centre have been able to reproduce clinical-type failures of the finger prostheses tested in them. This article describes the design and development of a finger simulator at Durham University, UK. It explains and justifies the engineering decisions made and thus the evolution of the finger simulator. In vitro results and their linkage to clinical-type failures are outlined to help to show the effectiveness of the simulator. Failures of finger implants in vivo continue to occur, and the need for appropriate in vitro testing of finger prostheses remains strong. PMID:26833697

  9. Numerical simulation and design of a thermionic electron gun

    NASA Astrophysics Data System (ADS)

    Hoseinzade, M.; Nijatie, M.; Sadighzadeh, A.

    2016-05-01

    This paper reports the simulation of an electron gun. The effects on the beam quality of some parameters on the beam quality were studied and optimal choices were identified. It gives numerical beam qualities for a common electrostatic triode gun, and the dependencies on design parameters such as electrode geometries and bias voltages to these electrodes are shown. An electron beam of diameter 5 mm with energy of 5 keV was assumed for the simulation process. Some design parameters were identified as variable parameters in the presence of space charge. These parameters are the inclination angle of emission electrode, the applied voltage to the focusing electrode, the gap width between the emission electrode and the focusing electrode and the diameter of the focusing electrode. The triode extraction system is designed and optimized by using CST software (for Particle Beam Simulations). The physical design of the extraction system is given in this paper. From the simulation results, it is concluded that the inclination angle of the emission electrode is optimized at 22.5°, the applied voltage to the focusing electrode was optimized and found to be V foc = ‑600 V, the optimal separation distance (gap between emission electrode and focusing electrode) is 4 mm, and the optimal diameter of the emission electrode is 14 mm. Initial results for these efforts aimed at emittance improvement are also given.

  10. Computer simulated plant design for waste minimization/pollution prevention

    SciTech Connect

    Bumble, S.

    2000-07-01

    The book discusses several paths to pollution prevention and waste minimization by using computer simulation programs. It explains new computer technologies used in the field of pollution prevention and waste management; provides information pertaining to overcoming technical, economic, and environmental barriers to waste reduction; gives case-studies from industries; and covers computer aided flow sheet design and analysis for nuclear fuel reprocessing.

  11. Design and numerical simulation of an optofluidic pressure sensor.

    PubMed

    Ebnali-Heidari, Majid; Mansouri, Morteza; Mokhtarian, Saeed; Moravvej-Farshi, Mohammed Kazem

    2012-06-01

    We present a numerical design procedure for an all-optical compact sensor by means of integrating the optofluidic switch polymer interferometers to measure the microfluidic air pressure and flow rate. The design is based on a flexible air gap optical cavity that can generate an interference pattern when illuminated by a monochromatic light. The optical interference pattern directly depends on the pressure. In our numerical simulations, we take the effects of fluid flow rate, solid deformation, and the light interference into account. We use the beam propagation method for simulating the optics and the finite element method for simulating the mechanics. The significance of the proposed sensor lies with its low power consumption, compactness, low cost, and short length. This sensor can operate under pressure range of 0-60±6%  Pa at a constant temperature of 20 °C. PMID:22695574

  12. ASPP2 Is a Novel Pan-Ras Nanocluster Scaffold

    PubMed Central

    Posada, Itziar M. D.; Serulla, Marc; Zhou, Yong; Oetken-Lindholm, Christina

    2016-01-01

    Ras-induced senescence mediated through ASPP2 represents a barrier to tumour formation. It is initiated by ASPP2’s interaction with Ras at the plasma membrane, which stimulates the Raf/MEK/ERK signaling cascade. Ras to Raf signalling requires Ras to be organized in nanoscale signalling complexes, called nanocluster. We therefore wanted to investigate whether ASPP2 affects Ras nanoclustering. Here we show that ASPP2 increases the nanoscale clustering of all oncogenic Ras isoforms, H-ras, K-ras and N-ras. Structure-function analysis with ASPP2 truncation mutants suggests that the nanocluster scaffolding activity of ASPP2 converges on its α-helical domain. While ASPP2 increased effector recruitment and stimulated ERK and AKT phosphorylation, it did not increase colony formation of RasG12V transformed NIH/3T3 cells. By contrast, ASPP2 was able to suppress the transformation enhancing ability of the nanocluster scaffold Gal-1, by competing with the specific effect of Gal-1 on H-rasG12V- and K-rasG12V-nanoclustering, thus imposing ASPP2’s ERK and AKT signalling signature. Similarly, ASPP2 robustly induced senescence and strongly abrogated mammosphere formation irrespective of whether it was expressed alone or together with Gal-1, which by itself showed the opposite effect in Ras wt or H-ras mutant breast cancer cells. Our results suggest that Gal-1 and ASPP2 functionally compete in nanocluster for active Ras on the plasma membrane. ASPP2 dominates the biological outcome, thus switching from a Gal-1 supported growth-promoting setting to a senescence inducing and stemness suppressive program in cancer cells. Our results support Ras nanocluster as major integrators of tumour fate decision events. PMID:27437940

  13. Design and Simulation of an Anode Stalk Support Insulator

    SciTech Connect

    Wang, L; Houck, T; Westenskow, G

    2005-05-16

    An anode stalk support insulator in a magnetically insulated transmission line was designed and modeled. One of the important design criteria is that within space constraints, the electric field along the insulator surface has to be minimized in order to prevent a surface flashover. In order to further reduce the field on the insulator surface, metal rings between insulator layers were also specially shaped. To facilitate the design process, electric field simulations were performed to determine the maximum field stress on the insulator surfaces and the transmission line chamber.

  14. Study, simulation and design of a 3D clinostat

    NASA Astrophysics Data System (ADS)

    Pavone, Valentina; Guarnieri, Vincenzo; Lobascio, Cesare; Soma, Aurelio; Bosso, Nicola; Lamantea, Matteo Maria

    High cost and limited number of physically executable experiments in space have introduced the need for ground simulation systems that enable preparing experiments to be carried out on board, identifying phenomena associated with the altered gravity conditions, and taking advantage of these conditions, as in Biotechnology. Among systems developed to simulate microgravity, especially for life sciences experiments, different types of clinostats were realized. This work deals with mechanical design of a three-dimensional clinostat and simulation of the dynamic behavior of the system by varying the operating parameters. The design and simulation phase was preceded by a careful analysis of the state of art and by the review of the most recent results, in particular from the major investigators of Life Sciences in Space. The mechanical design is quite innovative by adoption of a structure entirely in aluminum, which allows robustness while reducing the overall weight. The transmission system of motion has been optimized by means of brushless DC micro motors, light and compact, which helped to reduce weight, dimensions, power consumption and increase the reliability and durability of the system. The study of the dynamic behavior using SIMPACK, a multibody simulation software, led to results in line with those found in the most important and recent scientific publications. This model was also appropriately configured to represent any desired operating condition, and for eventual system scalability. It would be interesting to generate simulated hypogravity - e.g.: 0.38-g (Mars) or 0.17-g (Moon). This would allow to investigate how terrestrial life forms can grow in other planetary habitats, or to determine the gravity threshold response of different organisms. At the moment, such a system can only be achieved by centrifuges in real microgravity. We are confident that simulation and associated tests with our 3D clinostat can help adjusting the parameters allowing variable g

  15. Cosmic reionization on computers. I. Design and calibration of simulations

    SciTech Connect

    Gnedin, Nickolay Y.

    2014-09-20

    Cosmic Reionization On Computers is a long-term program of numerical simulations of cosmic reionization. Its goal is to model fully self-consistently (albeit not necessarily from the first principles) all relevant physics, from radiative transfer to gas dynamics and star formation, in simulation volumes of up to 100 comoving Mpc, and with spatial resolution approaching 100 pc in physical units. In this method paper, we describe our numerical method, the design of simulations, and the calibration of numerical parameters. Using several sets (ensembles) of simulations in 20 h {sup –1} Mpc and 40 h {sup –1} Mpc boxes with spatial resolution reaching 125 pc at z = 6, we are able to match the observed galaxy UV luminosity functions at all redshifts between 6 and 10, as well as obtain reasonable agreement with the observational measurements of the Gunn-Peterson optical depth at z < 6.

  16. Design of Accelerator Online Simulator Server Using Structured Data

    SciTech Connect

    Shen, Guobao; Chu, Chungming; Wu, Juhao; Kraimer, Martin; /Argonne

    2012-07-06

    Model based control plays an important role for a modern accelerator during beam commissioning, beam study, and even daily operation. With a realistic model, beam behaviour can be predicted and therefore effectively controlled. The approach used by most current high level application environments is to use a built-in simulation engine and feed a realistic model into that simulation engine. Instead of this traditional monolithic structure, a new approach using a client-server architecture is under development. An on-line simulator server is accessed via network accessible structured data. With this approach, a user can easily access multiple simulation codes. This paper describes the design, implementation, and current status of PVData, which defines the structured data, and PVAccess, which provides network access to the structured data.

  17. RAS one-equation turbulence model with non-singular eddy-viscosity coefficient

    NASA Astrophysics Data System (ADS)

    Rahman, M. M.; Agarwal, R. K.; Siikonen, T.

    2016-02-01

    A simplified consistency formulation for Pk/ε (production to dissipation ratio) is devised to obtain a non-singular Cμ (coefficient of eddy-viscosity) in the explicit algebraic Reynolds stress model of Gatski and Speziale. The coefficient Cμ depends non-linearly on both rotational/irrotational strains and is used in the framework of an improved RAS (Rahman-Agarwal-Siikonen) one-equation turbulence model to calculate a few well-documented turbulent flows, yielding predictions in good agreement with the direct numerical simulation and experimental data. The strain-dependent Cμ assists the RAS model in constructing the coefficients and functions such as to benefit complex flows with non-equilibrium turbulence. Comparisons with the Spalart-Allmaras one-equation model and the shear stress transport k-ω model demonstrate that Cμ improves the response of RAS model to non-equilibrium effects.

  18. Computational Aerodynamic Simulations of a Spacecraft Cabin Ventilation Fan Design

    NASA Technical Reports Server (NTRS)

    Tweedt, Daniel L.

    2010-01-01

    Quieter working environments for astronauts are needed if future long-duration space exploration missions are to be safe and productive. Ventilation and payload cooling fans are known to be dominant sources of noise, with the International Space Station being a good case in point. To address this issue cost effectively, early attention to fan design, selection, and installation has been recommended, leading to an effort by NASA to examine the potential for small-fan noise reduction by improving fan aerodynamic design. As a preliminary part of that effort, the aerodynamics of a cabin ventilation fan designed by Hamilton Sundstrand has been simulated using computational fluid dynamics codes, and the computed solutions analyzed to quantify various aspects of the fan aerodynamics and performance. Four simulations were performed at the design rotational speed: two at the design flow rate and two at off-design flow rates. Following a brief discussion of the computational codes, various aerodynamic- and performance-related quantities derived from the computed flow fields are presented along with relevant flow field details. The results show that the computed fan performance is in generally good agreement with stated design goals.

  19. Integrated Simulation Design Challenges to Support TPS Repair Operations

    NASA Technical Reports Server (NTRS)

    Quiocho, Leslie J.; Crues, Edwin Z.; Huynh, An; Nguyen, Hung T.; MacLean, John

    2005-01-01

    During the Orbiter Repair Maneuver (ORM) operations planned for Return to Flight (RTF), the Shuttle Remote Manipulator System (SRMS) must grapple the International Space Station (ISS), undock the Orbiter, maneuver it through a long duration trajectory, and orient it to an EVA crewman poised at the end of the Space Station Remote Manipulator System (SSRMS) to facilitate the repair of the Thermal Protection System (TPS). Once repair has been completed and confirmed, then the SRMS proceeds back through the trajectory to dock the Orbiter to the Orbiter Docking System. In order to support analysis of the complex dynamic interactions of the integrated system formed by the Orbiter, ISS, SRMS, and SSRMS during the ORM, simulation tools used for previous 'nominal' mission support required substantial enhancements. These upgrades were necessary to provide analysts with the capabilities needed to study integrated system performance. This paper discusses the simulation design challenges encountered while developing simulation capabilities to mirror the ORM operations. The paper also describes the incremental build approach that was utilized, starting with the subsystem simulation elements and integration into increasing more complex simulations until the resulting ORM worksite dynamics simulation had been assembled. Furthermore, the paper presents an overall integrated simulation V&V methodology based upon a subsystem level testing, integrated comparisons, and phased checkout.

  20. Superoxide Inhibits Guanine Nucleotide Exchange Factor (GEF) Action on Ras, but not on Rho, through Desensitization of Ras to GEF

    PubMed Central

    2015-01-01

    Ras and Rho GTPases are molecular switches for various vital cellular signaling pathways. Overactivation of these GTPases often causes development of cancer. Guanine nucleotide exchange factors (GEFs) and oxidants function to upregulate these GTPases through facilitation of guanine nucleotide exchange (GNE) of these GTPases. However, the effect of oxidants on GEF functions, or vice versa, has not been known. We show that, via targeting Ras Cys51, an oxidant inhibits the catalytic action of Cdc25—the catalytic domain of RasGEFs—on Ras. However, the enhancement of Ras GNE by an oxidant continues regardless of the presence of Cdc25. Limiting RasGEF action by an oxidant may function to prevent the pathophysiological overactivation of Ras in the presence of both RasGEFs and oxidants. The continuous exposure of Ras to nitric oxide and its derivatives can form S-nitrosated Ras (Ras-SNO). This study also shows that an oxidant not only inhibits the catalytic action of Cdc25 on Ras-SNO but also fails to enhance Ras-SNO GNE. This lack of enhancement then populates the biologically inactive Ras-SNO in cells, which may function to prevent the continued redox signaling of the Ras pathophysiological response. Finally, this study also demonstrates that, unlike the case with RasGEFs, an oxidant does not inhibit the catalytic action of RhoGEF—Vav or Dbs—on Rho GTPases such as Rac1, RhoA, RhoC, and Cdc42. This result explains the results of the previous study in which, despite the presence of an oxidant, the catalytic action of Dbs in cells continued to enhance RhoC GNE. PMID:24422478

  1. Comparing simulated emission from molecular clouds using experimental design

    SciTech Connect

    Yeremi, Miayan; Flynn, Mallory; Loeppky, Jason; Rosolowsky, Erik; Offner, Stella

    2014-03-10

    We propose a new approach to comparing simulated observations that enables us to determine the significance of the underlying physical effects. We utilize the methodology of experimental design, a subfield of statistical analysis, to establish a framework for comparing simulated position-position-velocity data cubes to each other. We propose three similarity metrics based on methods described in the literature: principal component analysis, the spectral correlation function, and the Cramer multi-variate two-sample similarity statistic. Using these metrics, we intercompare a suite of mock observational data of molecular clouds generated from magnetohydrodynamic simulations with varying physical conditions. Using this framework, we show that all three metrics are sensitive to changing Mach number and temperature in the simulation sets, but cannot detect changes in magnetic field strength and initial velocity spectrum. We highlight the shortcomings of one-factor-at-a-time designs commonly used in astrophysics and propose fractional factorial designs as a means to rigorously examine the effects of changing physical properties while minimizing the investment of computational resources.

  2. Parachute system design, analysis, and simulation tool. Status report

    SciTech Connect

    Sundberg, W.D.; McBride, D.D.; Gwinn, K.W.; Waye, D.E.; Hailey, C.E.

    1992-12-31

    For over twenty years designers at Sandia National Laboratories have developed various parachute simulation codes to model deployment, inflation, loading, trajectories, aircraft downwash and line sail. In addition to these codes, material property data bases have been acquired. Recently we have initiated project to integrate these codes and data bases into a single software tool entitled SPARSYS (Sandia PARachute SYstem Simulation). We have constructed a graphical user interface as the driver and framework for SPARSYS. In this paper we present a status report on SPARSYS describing progress in developing and incorporating independent modules, in developing an integrated trajectory package, and in developing a materials data base including high-rate-of-strain data.

  3. The Differential Palmitoylation States of N-Ras and H-Ras Determine Their Distinct Golgi Sub-compartment Localizations

    PubMed Central

    Lynch, Stephen J.; Snitkin, Harriet; Gumper, Iwona; Philips, Mark R.; Sabatini, David; Pellicer, Angel

    2014-01-01

    Despite a high degree of structural homology and shared exchange factors, effectors and GTPase activating proteins, a large body of evidence suggests functional heterogeneity among Ras isoforms. One aspect of Ras biology that may explain this heterogeneity is the differential subcellular localizations driven by the C-terminal hypervariable regions of Ras proteins. Spatial heterogeneity has been documented at the level of organelles: palmitoylated Ras isoforms (H-Ras and N-Ras) localize on the Golgi apparatus whereas K-Ras4B does not. We tested the hypothesis that spatial heterogeneity also exists at the sub-organelle level by studying the localization of differentially palmitoylated Ras isoforms within the Golgi apparatus. Using confocal, live cell fluorescent imaging and immunogold electron microscopy we found that, whereas the doubly palmitoylated H-Ras is distributed throughout the Golgi stacks, the singly palmitoylated N-Ras is polarized with a relative paucity of expression on the trans Golgi. Using palmitoylation mutants we show that the different sub-Golgi distributions of the Ras proteins are a consequence of their differential degree of palmitoylation. Thus, the acylation state of Ras proteins controls not only their distribution between the Golgi apparatus and the plasma membrane but also their distribution within the Golgi stacks. PMID:25158650

  4. Simulation-Guided DNA Probe Design for Consistently Ultraspecific Hybridization

    PubMed Central

    Wang, J. Sherry; Zhang, David Yu

    2015-01-01

    Hybridization of complementary sequences is one of the central tenets of nucleic acid chemistry; however, the unintended binding of closely related sequences limits the accuracy of hybridization-based approaches for analyzing nucleic acids. Thermodynamics-guided probe design and empirical optimization of reaction conditions have been used to enable discrimination of single nucleotide variants, but typically these approaches provide only an approximate 25-fold difference in binding affinity. Here we show that simulations of the binding kinetics are both necessary and sufficient to design nucleic acid probe systems with consistently high specificity as they enable the discovery of an optimal combination of thermodynamic parameters. Simulation-guided probe systems designed against 44 different target single nucleotide variants sequences showed between 200- and 3000-fold (median 890) higher binding affinity than their corresponding wildtype sequences. As a demonstration of the usefulness of this simulation-guided design approach we developed probes which, in combination with PCR amplification, we use to detect low concentrations of variant alleles (1%) in human genomic DNA. PMID:26100802

  5. Parametric design methodology for chemical processes using a simulator

    SciTech Connect

    Diwekar, U.M.; Rubin, E.S. )

    1994-02-01

    Parameter design is a method popularized by the Japanese quality expert G. Taguchi, for designing products and manufacturing processes that are robust in the face of uncontrollable variations. At the design stage, the goal of parameter design is to identify design settings that make the product performance less sensitive to the effects of manufacturing and environmental variations and deterioration. Because parameter design reduces performance variation by reducing the influence of the sources of variation rather than by controlling them, it is a cost-effective technique for improving quality. A recent study on the application of parameter design methodology for chemical processes reported that the use of Taguchi's method was not justified and a method based on Monte Carlo simulation combined with optimization was shown to be more effective. However, this method is computationally intensive as a large number of samples are necessary to achieve the given accuracy. Additionally, determination of the number of sample runs required is based on experimentation due to a lack of systematic sampling methods. In an attempt to overcome these problems, the use of a stochastic modeling capability combined with an optimizer is presented in this paper. The objective is that of providing an effective means for application of parameter design methodologies to chemical processes using the ASPEN simulator. This implementation not only presents a generalized tool for use by chemical engineers at large but also provides systematic estimates of the number of sample runs required to attain the specified accuracy. The stochastic model employs the technique of Latin hypercube sampling instead of the traditional Monte Carlo technique and hence has a great potential to reduce the required number of samples. The methodology is illustrated via an example problem of designing a chemical process.

  6. The Design and Implementation of the Swim Integrated Plasma Simulator

    SciTech Connect

    Elwasif, Wael R; Bernholdt, David E; Shet, Aniruddha G; Foley, Samantha S; Bramley, Randall B; Batchelor, Donald B; Berry, Lee A

    2010-01-01

    As computing capabilities have increased, the coupling of computational models has become an increasingly viable and therefore important way of improving the physical fidelity of simulations. Applications currently using some form of multicode or multi-component coupling include climate modeling, rocket simulations, and chemistry. In recent years, the plasma physics community has also begun to pursue integrated multiphysics simulations for space weather and fusion energy applications. Such model coupling generally exposes new issues in the physical, mathematical, and computational aspects of the problem. This paper focuses on the computational aspects of one such effort, detailing the design, and implementation of the Integrated Plasma Simulator (IPS) for the Center for Simulation of Wave Interactions with Magnetohydrodynamics (SWIM). The IPS framework focuses on maximizing flexibility for the creators of loosely-coupled component-based simulations, and provides services for execution coordination, resource management, data management, and inter-component communication. It also serves as a proving ground for a concurrent 'multi-tasking' execution model to improve resource utilization, and application-level fault tolerance. We also briefly describe how the IPS has been applied to several problems of interest to the fusion community.

  7. Design of 3D simulation engine for oilfield safety training

    NASA Astrophysics Data System (ADS)

    Li, Hua-Ming; Kang, Bao-Sheng

    2015-03-01

    Aiming at the demand for rapid custom development of 3D simulation system for oilfield safety training, this paper designs and implements a 3D simulation engine based on script-driven method, multi-layer structure, pre-defined entity objects and high-level tools such as scene editor, script editor, program loader. A scripting language been defined to control the system's progress, events and operating results. Training teacher can use this engine to edit 3D virtual scenes, set the properties of entity objects, define the logic script of task, and produce a 3D simulation training system without any skills of programming. Through expanding entity class, this engine can be quickly applied to other virtual training areas.

  8. Dedicated software for diffractive optics design and simulation

    NASA Astrophysics Data System (ADS)

    Firsov, A.; Brzhezinskaya, M.; Firsov, A.; Svintsov, A.; Erko, A.

    2013-03-01

    An efficient software package for the structure design and simulation of imaging properties of diffraction optical elements has been developed. It operates with point source and consists of: the ZON software, to calculate the structure of an optical element in transmission and reflection; the KRGF software, to simulate the diffraction properties of an ideal optical element with point source; the DS software, to calculate the diffraction properties by taking into consideration material and shadowing effects. Optional software allows simulation with a real non-point source. Zone plate thickness profile, source shape as well as substrate curvature are considered in this calculation. This is especially important for the diffractive focusing elements and gratings at a total external reflection, given that the lateral size of the structure can be up to 1 m. The program package can be used in combination with the Nanomaker software to prepare data for ion and e-beam surface modifications and corrections.

  9. Programmable multi-node quantum network design and simulation

    NASA Astrophysics Data System (ADS)

    Dasari, Venkat R.; Sadlier, Ronald J.; Prout, Ryan; Williams, Brian P.; Humble, Travis S.

    2016-05-01

    Software-defined networking offers a device-agnostic programmable framework to encode new network functions. Externally centralized control plane intelligence allows programmers to write network applications and to build functional network designs. OpenFlow is a key protocol widely adopted to build programmable networks because of its programmability, flexibility and ability to interconnect heterogeneous network devices. We simulate the functional topology of a multi-node quantum network that uses programmable network principles to manage quantum metadata for protocols such as teleportation, superdense coding, and quantum key distribution. We first show how the OpenFlow protocol can manage the quantum metadata needed to control the quantum channel. We then use numerical simulation to demonstrate robust programmability of a quantum switch via the OpenFlow network controller while executing an application of superdense coding. We describe the software framework implemented to carry out these simulations and we discuss near-term efforts to realize these applications.

  10. Design concepts to improve high performance solar simulator

    NASA Technical Reports Server (NTRS)

    Juranek, H. J.; Frey, H. U.

    1986-01-01

    By improving several important components of the well known off-axis solar simulator system, a considerable step forward was made. The careful mathematical studies on the optics and the thermal side of the problem lead to a highly efficient system with low operational costs and a high reliability. The actual performance of the simulator is significantly better than the specified one, and the efficiency is outstanding. No more than 12 lamps operating at 18 kW are required to obtain one Solar Constant in the 6 m beam. It is now known that by using sophisticated optics, even larger facilities of high performance can be designed without leaving the proven off-axis concept and using a spherical mirror. Using high performance optics is a means of reducing costs at a given size of beam because the number of lamps is one of the most cost driving factors in the construction of a solar simulator.

  11. An automated methodology development. [software design for combat simulation

    NASA Technical Reports Server (NTRS)

    Hawley, L. R.

    1985-01-01

    The design methodology employed in testing the applicability of Ada in large-scale combat simulations is described. Ada was considered as a substitute for FORTRAN to lower life cycle costs and ease the program development efforts. An object-oriented approach was taken, which featured definitions of military targets, the capability of manipulating their condition in real-time, and one-to-one correlation between the object states and real world states. The simulation design process was automated by the problem statement language (PSL)/problem statement analyzer (PSA). The PSL/PSA system accessed the problem data base directly to enhance the code efficiency by, e.g., eliminating non-used subroutines, and provided for automated report generation, besides allowing for functional and interface descriptions. The ways in which the methodology satisfied the responsiveness, reliability, transportability, modifiability, timeliness and efficiency goals are discussed.

  12. Design and Simulation of Microwave Attenuators for Superconducting Quantum Devices

    NASA Astrophysics Data System (ADS)

    Lefebvre, Jay; Yeh, Jen-Hao; Wellstood, Frederick; Palmer, Benjamin

    We have found that dephasing times for quantum superconducting transmons operating nominally at T = 20 mK can be limited by thermal photons in the read-out cavity due to non-equilibrium noise on our input microwave line. In an effort to reduce this noise, we have used finite-element simulations to design attenuators that provide better thermalization of the input microwave signals being delivered to our devices. Our thermal simulations incorporate both electron-phonon decoupling effects due to dissipated power in each element of the attenuator as well as phonon thermal conduction and Kapitza boundary effects. We combine the resulting thermal map with a thermal noise model of each dissipative element of the filter to estimate the effective noise temperature of our filter design.

  13. VINCI Altitude Simulation - Vacuum Chamber Design and Manufacturing

    NASA Astrophysics Data System (ADS)

    Delrez, C.; Collin, B.; Chisogne, J.-P.; Amestoy, S.; Hardouin, E.

    2004-08-01

    a motor driven trolley, a raising/lowering system, The purpose of this article is to describe the design, computation, production and installation of a Simplified altitude Simulation (SAS) package intended for the VINCI engine tests on the PF52bench. a duct for connection to the ejector, an engine ignition viewing system a drive and power supply assembly, a set of measuring instruments, The simulation is used to reconstitute at ground level the same flying conditions as those normally found at the altitude where the Ariane 5 launcher cryogenic engine is fired. a control and monitoring assembly. This PF52 bench, which is being modified, is located on the Snecma Moteurs Space Engine division's test site, at Vernon (France). The design, computation, production and installation of the SAS are under the responsibility of the company AMOS sa, at Angleur (Belgium).

  14. Design and Simulation of a Valveless Micro Pump

    NASA Astrophysics Data System (ADS)

    Dau, Van Thanh; Dinh, Thien Xuan; Tanaka, Katsuhiko; Sugiyama, Susumu

    This paper reports on the design and simulation of a valveless micro pump which promises widely applicable in microfluidic applications. The structure of the pump comprises a PZT diaphragm and a fluidic network channel which can be easily fabricated by either conventional machining or silicon micromachining techniques. The working principle of the pump relies on the structure of the cross junction which connects the pump chamber, the outlet and two opposite inlet channels. This design allows a difference of fluidic resistance and momentum between the pump phases which results in a net flow from the inlet to outlet. The pump performance is studied by numerical simulation by applying the deformation of the PZT diaphragm. Experiments of the prototype had been conducted and working principle was confirmed.

  15. Simulation models and designs for advanced Fischer-Tropsch technology

    SciTech Connect

    Choi, G.N.; Kramer, S.J.; Tam, S.S.

    1995-12-31

    Process designs and economics were developed for three grass-roots indirect Fischer-Tropsch coal liquefaction facilities. A baseline and an alternate upgrading design were developed for a mine-mouth plant located in southern Illinois using Illinois No. 6 coal, and one for a mine-mouth plane located in Wyoming using Power River Basin coal. The alternate design used close-coupled ZSM-5 reactors to upgrade the vapor stream leaving the Fischer-Tropsch reactor. ASPEN process simulation models were developed for all three designs. These results have been reported previously. In this study, the ASPEN process simulation model was enhanced to improve the vapor/liquid equilibrium calculations for the products leaving the slurry bed Fischer-Tropsch reactors. This significantly improved the predictions for the alternate ZSM-5 upgrading design. Another model was developed for the Wyoming coal case using ZSM-5 upgrading of the Fischer-Tropsch reactor vapors. To date, this is the best indirect coal liquefaction case. Sensitivity studies showed that additional cost reductions are possible.

  16. Robust Multivariable Optimization and Performance Simulation for ASIC Design

    NASA Technical Reports Server (NTRS)

    DuMonthier, Jeffrey; Suarez, George

    2013-01-01

    Application-specific-integrated-circuit (ASIC) design for space applications involves multiple challenges of maximizing performance, minimizing power, and ensuring reliable operation in extreme environments. This is a complex multidimensional optimization problem, which must be solved early in the development cycle of a system due to the time required for testing and qualification severely limiting opportunities to modify and iterate. Manual design techniques, which generally involve simulation at one or a small number of corners with a very limited set of simultaneously variable parameters in order to make the problem tractable, are inefficient and not guaranteed to achieve the best possible results within the performance envelope defined by the process and environmental requirements. What is required is a means to automate design parameter variation, allow the designer to specify operational constraints and performance goals, and to analyze the results in a way that facilitates identifying the tradeoffs defining the performance envelope over the full set of process and environmental corner cases. The system developed by the Mixed Signal ASIC Group (MSAG) at the Goddard Space Flight Center is implemented as a framework of software modules, templates, and function libraries. It integrates CAD tools and a mathematical computing environment, and can be customized for new circuit designs with only a modest amount of effort as most common tasks are already encapsulated. Customization is required for simulation test benches to determine performance metrics and for cost function computation.

  17. Performance parameters in the design of flight motion simulators

    NASA Astrophysics Data System (ADS)

    Mitchell, Robert W.

    2012-06-01

    The desired test performance parameters influence the design of a Flight Motion Simulator (FMS) and affect its size, weight, power, electro-magnetic interference, noise, and vibration. A common desire is to specify requirements beyond the immediate need for future test programs. This may directly affect cost and schedule. Critical parameters that affect the FMS design are larger payload sizes, higher accuracies, and higher dynamic requirements. This paper provides a checklist of parameters and specification tradeoffs to be considered for the overall system performance requirements.

  18. Simulation Environment for Orion Launch Abort System Control Design Studies

    NASA Technical Reports Server (NTRS)

    McMinn, J. Dana; Jackson, E. Bruce; Christhilf, David M.

    2007-01-01

    The development and use of an interactive environment to perform control system design and analysis of the proposed Crew Exploration Vehicle Launch Abort System is described. The environment, built using a commercial dynamic systems design package, includes use of an open-source configuration control software tool and a collaborative wiki to coordinate between the simulation developers, control law developers and users. A method for switching between multiple candidate control laws and vehicle configurations is described. Aerodynamic models, especially in a development program, change rapidly, so a means for automating the implementation of new aerodynamic models is described.

  19. Computational studies of Ras and PI3K

    NASA Technical Reports Server (NTRS)

    Ren, Lei; Cucinotta, Francis A.

    2004-01-01

    Until recently, experimental techniques in molecular cell biology have been the primary means to investigate biological risk upon space radiation. However, computational modeling provides an alternative theoretical approach, which utilizes various computational tools to simulate proteins, nucleotides, and their interactions. In this study, we are focused on using molecular mechanics (MM) and molecular dynamics (MD) to study the mechanism of protein-protein binding and to estimate the binding free energy between proteins. Ras is a key element in a variety of cell processes, and its activation of phosphoinositide 3-kinase (PI3K) is important for survival of transformed cells. Different computational approaches for this particular study are presented to calculate the solvation energies and binding free energies of H-Ras and PI3K. The goal of this study is to establish computational methods to investigate the roles of different proteins played in the cellular responses to space radiation, including modification of protein function through gene mutation, and to support the studies in molecular cell biology and theoretical kinetics models for our risk assessment project.

  20. Inhibition of Ras for cancer treatment: the search continues

    PubMed Central

    Baines, Antonio T.; Xu, Dapeng; Der, Channing J.

    2012-01-01

    Background The RAS oncogenes (HRAS, NRAS and KRAS) comprise the most frequently mutated class of oncogenes in human cancers (33%), stimulating intensive effort in developing anti-Ras inhibitors for cancer treatment. Discussion Despite intensive effort, to date no effective anti-Ras strategies have successfully made it to the clinic. We present an overview of past and ongoing strategies to inhibit oncogenic Ras in cancer. Conclusions Since approaches to directly target mutant Ras have not been successful, most efforts have focused on indirect approaches to block Ras membrane association or downstream effector signaling. While inhibitors of effector signaling are currently under clinical evaluation, genome-wide unbiased genetic screens have identified novel directions for future anti-Ras drug discovery. PMID:22004085

  1. EGFR phosphorylates FAM129B to promote Ras activation

    PubMed Central

    Ji, Haitao; Lee, Jong-Ho; Wang, Yugang; Pang, Yilin; Zhang, Tao; Xia, Yan; Zhong, Lianjin; Lyu, Jianxin; Lu, Zhimin

    2016-01-01

    Ras GTPase-activating proteins (GAPs) are important regulators for Ras activation, which is instrumental in tumor development. However, the mechanism underlying this regulation remains elusive. We demonstrate here that activated EGFR phosphorylates the Y593 residue of the protein known as family with sequence similarity 129, member B (FAM129B), which is overexpressed in many types of human cancer. FAM129B phosphorylation increased the interaction between FAM129B and Ras, resulting in reduced binding of p120-RasGAP to Ras. FAM129B phosphorylation promoted Ras activation, increasing ERK1/2- and PKM2-dependent β-catenin transactivation and leading to the enhanced glycolytic gene expression and the Warburg effect; promoting tumor cell proliferation and invasion; and supporting brain tumorigenesis. Our studies unearthed a novel and important mechanism underlying EGFR-mediated Ras activation in tumor development. PMID:26721396

  2. Design, Fabrication, and Testing of a Hopper Spacecraft Simulator

    NASA Astrophysics Data System (ADS)

    Mucasey, Evan Phillip Krell

    A robust test bed is needed to facilitate future development of guidance, navigation, and control software for future vehicles capable of vertical takeoff and landings. Specifically, this work aims to develop both a hardware and software simulator that can be used for future flight software development for extra-planetary vehicles. To achieve the program requirements of a high thrust to weight ratio with large payload capability, the vehicle is designed to have a novel combination of electric motors and a micro jet engine is used to act as the propulsion elements. The spacecraft simulator underwent several iterations of hardware development using different materials and fabrication methods. The final design used a combination of carbon fiber and fiberglass that was cured under vacuum to serve as the frame of the vehicle which provided a strong, lightweight platform for all flight components and future payloads. The vehicle also uses an open source software development platform, Arduino, to serve as the initial flight computer and has onboard accelerometers, gyroscopes, and magnetometers to sense the vehicles attitude. To prevent instability due to noise, a polynomial kalman filter was designed and this fed the sensed angles and rates into a robust attitude controller which autonomously control the vehicle' s yaw, pitch, and roll angles. In addition to the hardware development of the vehicle itself, both a software simulation and a real time data acquisition interface was written in MATLAB/SIMULINK so that real flight data could be taken and then correlated to the simulation to prove the accuracy of the analytical model. In result, the full scale vehicle was designed and own outside of the lab environment and data showed that the software model accurately predicted the flight dynamics of the vehicle.

  3. The Structural Basis of Oncogenic Mutations G12, G13 and Q61 in Small GTPase K-Ras4B.

    PubMed

    Lu, Shaoyong; Jang, Hyunbum; Nussinov, Ruth; Zhang, Jian

    2016-01-01

    Ras mediates cell proliferation, survival and differentiation. Mutations in K-Ras4B are predominant at residues G12, G13 and Q61. Even though all impair GAP-assisted GTP → GDP hydrolysis, the mutation frequencies of K-Ras4B in human cancers vary. Here we aim to figure out their mechanisms and differential oncogenicity. In total, we performed 6.4 μs molecular dynamics simulations on the wild-type K-Ras4B (K-Ras4B(WT)-GTP/GDP) catalytic domain, the K-Ras4B(WT)-GTP-GAP complex, and the mutants (K-Ras4B(G12C/G12D/G12V)-GTP/GDP, K-Ras4B(G13D)-GTP/GDP, K-Ras4B(Q61H)-GTP/GDP) and their complexes with GAP. In addition, we simulated 'exchanged' nucleotide states. These comprehensive simulations reveal that in solution K-Ras4B(WT)-GTP exists in two, active and inactive, conformations. Oncogenic mutations differentially elicit an inactive-to-active conformational transition in K-Ras4B-GTP; in K-Ras4B(G12C/G12D)-GDP they expose the bound nucleotide which facilitates the GDP-to-GTP exchange. These mechanisms may help elucidate the differential mutational statistics in K-Ras4B-driven cancers. Exchanged nucleotide simulations reveal that the conformational transition is more accessible in the GTP-to-GDP than in the GDP-to-GTP exchange. Importantly, GAP not only donates its R789 arginine finger, but stabilizes the catalytically-competent conformation and pre-organizes catalytic residue Q61; mutations disturb the R789/Q61 organization, impairing GAP-mediated GTP hydrolysis. Together, our simulations help provide a mechanistic explanation of key mutational events in one of the most oncogenic proteins in cancer. PMID:26902995

  4. Design & simulation of in-plane MEMS Lorentz force magnetometer

    NASA Astrophysics Data System (ADS)

    Jyoti, Aditi, Tripathi, C. C.; Gopal, Ram

    2016-03-01

    This report presents the design and simulation of a MEMS based In-plane Lorentz Force Magnetometer (I-LFM), simulated for 8 um UV-LIGA technology using FEM tool of COMSOL Multiphysics 4.3b. Designed I-LFM was simulated in the magnetic field range varied from 1 μJT to 100μJT. The proposed structure composed of a comb drive actuator, configured such that the fingers overlap with each other to generate capacitive coupling for its actuation. The magnetic field can be detected in Z-axis by this comb drive structure. The device was excited by supplying the sinusoidal current with the frequency equivalent to resonance frequency of the device at its first mode i.e. 12.047 kHz. In order to achieve the maximum mechanical output, the device was operated at the resonant frequency. Simulations based results shows a good linearity in the magnetic field range of 1 μJT to 100 μJT with a high quality factor of 130.

  5. Computer simulations of realistic microstructures: Implications for simulation-based materials design

    NASA Astrophysics Data System (ADS)

    Singh, Harpreet

    The conventional route of materials development typically involves fabrication of numerous batches of specimens having a range of different microstructures generated via variations of process parameters and measurements of relevant properties of these microstructures to identify the combination of processing conditions that yield the material having desired properties. Clearly, such a trial and error based materials development methodology is expensive, time consuming, and inefficient. Consequently, it is of interest to explore alternate strategies that can lead to a decrease in the cost and time required for development of advanced materials such as composites. Availability of powerful and inexpensive computational power and progress in computational materials science permits advancement of modeling and simulations assisted materials design methodology that may require fewer experiments, and therefore, lower cost and time for materials development. The key facets of such a technology would be computational tools for (i) creating models to generate computer simulated realistic microstructures; (ii) capturing the process-microstructure relationship using these models; and (iii) implementation of simulated microstructures in the computational models for materials behavior. Therefore, development of a general and flexible methodology for simulations of realistic microstructures is crucial for the development of simulations based materials design and development technology. Accordingly, this research concerns development of such a methodology for simulations of realistic microstructures based on experimental quantitative stereological data on few microstructures that can capture relevant details of microstructural geometry (including spatial clustering and second phase particle orientations) and its variations with process parameters in terms of a set of simulation parameters. The interpolation and extrapolation of the simulation parameters can then permit generation

  6. Monte Carlo simulations for design of the KFUPM PGNAA facility

    NASA Astrophysics Data System (ADS)

    Naqvi, A. A.; Nagadi, M. M.; Khateeb-ur-Rehman; Maslehuddin, M.; Kidwai, S.

    2003-02-01

    Monte Carlo simulations were carried out to design a 2.8 MeV neutron-based prompt gamma ray neutron activation analysis (PGNAA) setup for elemental analysis of cement samples. The elemental analysis was carried out using prompt gamma rays produced through capture of thermal neutrons in sample nuclei. The basic design of the PGNAA setup consists of a cylindrical cement sample enclosed in a cylindrical high-density polyethylene moderator placed between a neutron source and a gamma ray detector. In these simulations the predominant geometrical parameters of the PGNAA setup were optimized, including moderator size, sample size and shielding of the detector. Using the results of the simulations, an experimental PGNAA setup was then fabricated at the 350 kV Accelerator Laboratory of this University. The design calculations were checked experimentally through thermal neutron flux measurements inside the PGNAA moderator. A test prompt gamma ray spectrum of the PGNAA setup was also acquired from a Portland cement sample, using a pulsed beam of 2.8 MeV neutrons. Prompt gamma ray peaks due to the calcium, silicon and iron content of the Portland cement were detected.

  7. Design and Simulation of an Electrothermal Actuator Based Rotational Drive

    NASA Astrophysics Data System (ADS)

    Beeson, Sterling; Dallas, Tim

    2008-10-01

    As a participant in the Micro and Nano Device Engineering (MANDE) Research Experience for Undergraduates program at Texas Tech University, I learned how MEMS devices operate and the limits of their operation. Using specialized AutoCAD-based design software and the ANSYS simulation program, I learned the MEMS fabrication process used at Sandia National Labs, the design limitations of this process, the abilities and drawbacks of micro devices, and finally, I redesigned a MEMS device called the Chevron Torsional Ratcheting Actuator (CTRA). Motion is achieved through electrothermal actuation. The chevron (bent-beam) actuators cause a ratcheting motion on top of a hub-less gear so that as voltage is applied the CTRA spins. The voltage applied needs to be pulsed and the frequency of the pulses determine the angular frequency of the device. The main objective was to design electromechanical structures capable of transforming the electrical signals into mechanical motion without overheating. The design was optimized using finite element analysis in ANSYS allowing multi-physics simulations of our model system.

  8. Design and Simulation of the nuSTORM Pion Beamline

    SciTech Connect

    Liu, A.; Neuffer, D.; Bross, A.

    2015-08-15

    The nuSTORM (neutrinos from STORed Muons) proposal presents a detailed design for a neutrino facility based on a muon storage ring, with muon decay in the production straight section of the ring providing well defined neutrino beams. The facility includes a primary high-energy proton beam line, a target station with pion production and collection, and a pion beamline for pion transportation and injection into a muon decay ring. The nuSTORM design uses “stochastic injection”, in which pions are directed by a chicane, referred to as the Orbit Combination Section (OCS), into the production straight section of the storage ring. Pions that decay within that straight section provide muons within the circulating acceptance of the ring. Furthermore, the design enables injection without kickers or a separate pion decay transport line. The beam line that the pions traverse before being extracted from the decay ring is referred to as the pion beamline. Our paper describes the design and simulation of the pion beamline, and includes full beam dynamics simulations of the system.

  9. Design and Simulation of the nuSTORM Pion Beamline

    DOE PAGESBeta

    Liu, A.; Neuffer, D.; Bross, A.

    2015-08-15

    The nuSTORM (neutrinos from STORed Muons) proposal presents a detailed design for a neutrino facility based on a muon storage ring, with muon decay in the production straight section of the ring providing well defined neutrino beams. The facility includes a primary high-energy proton beam line, a target station with pion production and collection, and a pion beamline for pion transportation and injection into a muon decay ring. The nuSTORM design uses “stochastic injection”, in which pions are directed by a chicane, referred to as the Orbit Combination Section (OCS), into the production straight section of the storage ring. Pionsmore » that decay within that straight section provide muons within the circulating acceptance of the ring. Furthermore, the design enables injection without kickers or a separate pion decay transport line. The beam line that the pions traverse before being extracted from the decay ring is referred to as the pion beamline. Our paper describes the design and simulation of the pion beamline, and includes full beam dynamics simulations of the system.« less

  10. Design and simulation of silicon photonic schematics and layouts

    NASA Astrophysics Data System (ADS)

    Chrostowski, Lukas; Lu, Zeqin; Flueckiger, Jonas; Wang, Xu; Klein, Jackson; Liu, Amy; Jhoja, Jaspreet; Pond, James

    2016-05-01

    Electronic circuit designers commonly start their design process with a schematic, namely an abstract representation of the physical circuit. In integrated photonics on the other hand, it is common for the design to begin at the physical component level, and create a layout by connecting components with interconnects. In this paper, we discuss how to create a schematic from the physical layout via netlist extraction, which enables circuit simulations. Post-layout extraction can also be used to predict how fabrication variability and non-uniformity will impact circuit performance. This is based on the component position information, compact models that are parameterized for dimensional variations, and manufacturing variability models such as a simulated wafer thickness map. This final step is critical in understanding how real-world silicon photonic circuits will behave. We present an example based on treating the ring resonator as a circuit. A silicon photonics design kit, as described here, is available for download at http://github.com/lukasc-ubc/SiEPIC_EBeam_PDK.

  11. Designing a Distributed Space Systems Simulation in Accordance with the Simulation Interoperability Standards Organization (SISO)

    NASA Technical Reports Server (NTRS)

    Cowen, Benjamin

    2011-01-01

    Simulations are essential for engineering design. These virtual realities provide characteristic data to scientists and engineers in order to understand the details and complications of the desired mission. A standard development simulation package known as Trick is used in developing a source code to model a component (federate in HLA terms). The runtime executive is integrated into an HLA based distributed simulation. TrickHLA is used to extend a Trick simulation for a federation execution, develop a source code for communication between federates, as well as foster data input and output. The project incorporates international cooperation along with team collaboration. Interactions among federates occur throughout the simulation, thereby relying on simulation interoperability. Communication through the semester went on between participants to figure out how to create this data exchange. The NASA intern team is designing a Lunar Rover federate and a Lunar Shuttle federate. The Lunar Rover federate supports transportation across the lunar surface and is essential for fostering interactions with other federates on the lunar surface (Lunar Shuttle, Lunar Base Supply Depot and Mobile ISRU Plant) as well as transporting materials to the desired locations. The Lunar Shuttle federate transports materials to and from lunar orbit. Materials that it takes to the supply depot include fuel and cargo necessary to continue moon-base operations. This project analyzes modeling and simulation technologies as well as simulation interoperability. Each team from participating universities will work on and engineer their own federate(s) to participate in the SISO Spring 2011 Workshop SIW Smackdown in Boston, Massachusetts. This paper will focus on the Lunar Rover federate.

  12. Design and simulation of the nuSTORM facility

    SciTech Connect

    Liu, Ao

    2015-04-01

    This thesis provides a full design and simulation of the nuSTORM beam line facility including the pion beam line , the pion and muon orbit combination section, and the muon decay ring. The study also includes the development of numerical optimization methods and their application to the design. At nuSTORM, one proton batch from the Main Injector (MI) is extracted and transported to the target station to bombard a solid target. A magnetic horn is used as the collection device for the secondary particles such as pions and kaons. A pion beam line is designed to transport the secondary particles downstream to the muon decay ring. In order to avoid the use of a fast kicker with a large aperture for the injection, an Orbit Combination Section (OCS) was designed to combine the reference pion orbit with the circulating muon orbit. This ful lls the stochastic injection scheme proposed in the 1980s. It is shown through the simulation that the pion beam line is able to deliver 0.011 muons per proton on target within the acceptance of the ring. In order to improve the circulating muon ux, an optimization of the magnetic collection horn was studied. A Multi-Objective Genetic Algorithm (MOGA), that was modi ed to integrate Message Passing Interface (MPI) in the process, is applied to the optimization. The number of muons within the ring acceptance from the pion decay is estimated by the pions after the collection horn. This new method was proposed to lower the requirement on the computing resources for the optimization. The study gives a new and better target and horn con guration after a full investigation of the system. The nuSTORM ring is examined with two optics designs. With di erent features, the two designs are optimized via correcting the nonlinearities with sextupolar eld distribution in the ring. A modi ed MPI-based Simulated Annealing (SA) algorithm was applied to obtain the optimal ring acceptance. The comparison with the GA shows good agreements on the achieved

  13. Guiding without feeling guided: Implicit scaffolding through interactive simulation design

    NASA Astrophysics Data System (ADS)

    Paul, Ariel; Podolefsky, Noah; Perkins, Katherine

    2013-01-01

    While PhET interactive simulations (sims) were historically designed for college students, they are used at lower grade levels, and we are currently developing sims targeted at middle school (MS). In studying how MS students interact with and learn from these sims, we have been extracting insights about design for the middle-grade-levels and across K-16. This collection of work has highlighted the importance of implicit scaffolding, a design framework that reduces the amount of explicit instruction needed to facilitate learning. We present a case study of redesigning a sim - Energy Skate Park (ESP) - for effective use in MS. We conducted think-aloud interviews with MS students to identify successful features, sources of confusion or unproductive distraction, as well as features inconsistent with gradeappropriate learning goals. Drawing on these data and the principle of implicit scaffolding, we developed Energy Skate Park Basics (ESPB). Interviews on ESPB demonstrate increased usability and learning for MS students.

  14. RAS Mutations and Oncogenesis: Not all RAS Mutations are Created Equally

    PubMed Central

    Miller, Mark Steven; Miller, Lance D.

    2012-01-01

    Mutation in RAS proteins is one of the most common genetic alterations observed in human and experimentally induced rodent cancers. In vivo, oncogenic mutations have been shown to occur at exons 12, 13, and 61, resulting in any 1 of 19 possible point mutations in a given tumor for a specific RAS isoform. While some studies have suggested a possible role of different mutant alleles in determining tumor severity and phenotype, no general consensus has emerged on the oncogenicity of different mutant alleles in tumor formation and progression. Part of this may be due to a lack of a single, signature pathway that shows significant alterations between different mutations. Rather, it is likely that subtle differences in the activation, or lack thereof, of downstream effectors by different RAS mutant alleles may determine the eventual outcome in terms of tumor phenotype. This paper reviews our current understanding of the potential role of different RAS mutations on tumorigenesis, highlights studies in model cell culture and in vivo systems, and discusses the potential of expression array and computational network modeling to dissect out differences in activated RAS genes in conferring a transforming phenotype. PMID:22303394

  15. Ras Family Small GTPase-mediated Neuroprotective Signaling in Stroke

    PubMed Central

    Shi, Geng-Xian; Andres, Douglas A.; Cai, Weikang

    2012-01-01

    Selective neuronal cell death is one of the major causes of neuronal damage following stroke, and cerebral cells naturally mobilize diverse survival signaling pathways to protect against ischemia. Importantly, therapeutic strategies designed to improve endogenous anti-apoptotic signaling appear to hold great promise in stroke treatment. While a variety of complex mechanisms have been implicated in the pathogenesis of stroke, the overall mechanisms governing the balance between cell survival and death are not well-defined. Ras family small GTPases are activated following ischemic insults, and in turn, serve as intrinsic switches to regulate neuronal survival and regeneration. Their ability to integrate diverse intracellular signal transduction pathways makes them critical regulators and potential therapeutic targets for neuronal recovery after stroke. This article highlights the contribution of Ras family GTPases to neuroprotective signaling cascades, including mitogen-activated protein kinase (MAPK) family protein kinase- and AKT/PKB-dependent signaling pathways as well as the regulation of cAMP response element binding (CREB), Forkhead box O (FoxO) and hypoxia-inducible factor 1(HIF1) transcription factors, in stroke. PMID:21521171

  16. Designing laboratory wind simulations using artificial neural networks

    NASA Astrophysics Data System (ADS)

    Križan, Josip; Gašparac, Goran; Kozmar, Hrvoje; Antonić, Oleg; Grisogono, Branko

    2015-05-01

    While experiments in boundary layer wind tunnels remain to be a major research tool in wind engineering and environmental aerodynamics, designing the modeling hardware required for a proper atmospheric boundary layer (ABL) simulation can be costly and time consuming. Hence, possibilities are sought to speed-up this process and make it more time-efficient. In this study, two artificial neural networks (ANNs) are developed to determine an optimal design of the Counihan hardware, i.e., castellated barrier wall, vortex generators, and surface roughness, in order to simulate the ABL flow developing above urban, suburban, and rural terrains, as previous ANN models were created for one terrain type only. A standard procedure is used in developing those two ANNs in order to further enhance best-practice possibilities rather than to improve existing ANN designing methodology. In total, experimental results obtained using 23 different hardware setups are used when creating ANNs. In those tests, basic barrier height, barrier castellation height, spacing density, and height of surface roughness elements are the parameters that were varied to create satisfactory ABL simulations. The first ANN was used for the estimation of mean wind velocity, turbulent Reynolds stress, turbulence intensity, and length scales, while the second one was used for the estimation of the power spectral density of velocity fluctuations. This extensive set of studied flow and turbulence parameters is unmatched in comparison to the previous relevant studies, as it includes here turbulence intensity and power spectral density of velocity fluctuations in all three directions, as well as the Reynolds stress profiles and turbulence length scales. Modeling results agree well with experiments for all terrain types, particularly in the lower ABL within the height range of the most engineering structures, while exhibiting sensitivity to abrupt changes and data scattering in profiles of wind-tunnel results. The

  17. Design, modeling, simulation and evaluation of a distributed energy system

    NASA Astrophysics Data System (ADS)

    Cultura, Ambrosio B., II

    This dissertation presents the design, modeling, simulation and evaluation of distributed energy resources (DER) consisting of photovoltaics (PV), wind turbines, batteries, a PEM fuel cell and supercapacitors. The distributed energy resources installed at UMass Lowell consist of the following: 2.5kW PV, 44kWhr lead acid batteries and 1500W, 500W & 300W wind turbines, which were installed before year 2000. Recently added to that are the following: 10.56 kW PV array, 2.4 kW wind turbine, 29 kWhr Lead acid batteries, a 1.2 kW PEM fuel cell and 4-140F supercapacitors. Each newly added energy resource has been designed, modeled, simulated and evaluated before its integration into the existing PV/Wind grid-connected system. The Mathematical and Simulink model of each system was derived and validated by comparing the simulated and experimental results. The Simulated results of energy generated from a 10.56kW PV system are in good agreement with the experimental results. A detailed electrical model of a 2.4kW wind turbine system equipped with a permanent magnet generator, diode rectifier, boost converter and inverter is presented. The analysis of the results demonstrates the effectiveness of the constructed simulink model, and can be used to predict the performance of the wind turbine. It was observed that a PEM fuel cell has a very fast response to load changes. Moreover, the model has validated the actual operation of the PEM fuel cell, showing that the simulated results in Matlab Simulink are consistent with the experimental results. The equivalent mathematical equation, derived from an electrical model of the supercapacitor, is used to simulate its voltage response. The model is completely capable of simulating its voltage behavior, and can predict the charge time and discharge time of voltages on the supercapacitor. The bi-directional dc-dc converter was designed in order to connect the 48V battery bank storage to the 24V battery bank storage. This connection was

  18. An approximate simulation model for initial luge track design.

    PubMed

    Mössner, Martin; Hasler, Michael; Schindelwig, Kurt; Kaps, Peter; Nachbauer, Werner

    2011-03-15

    Competitive and recreational sport on artificial ice tracks has grown in popularity. For track design one needs knowledge of the expected speed and acceleration of the luge on the ice track. The purpose of this study was to develop an approximate simulation model for luge in order to support the initial design of new ice tracks. Forces considered were weight, drag, friction, and surface reaction force. The trajectory of the luge on the ice track was estimated using a quasi-static force balance and a 1d equation of motion was solved along that trajectory. The drag area and the coefficient of friction for two runs were determined by parameter identification using split times of five sections of the Whistler Olympic ice track. The values obtained agreed with experimental data from ice friction and wind tunnel measurements. To validate the ability of the model to predict speed and accelerations normal to the track surface, a luge was equipped with an accelerometer to record the normal acceleration during the entire run. Simulated and measured normal accelerations agreed well. In a parameter study the vertical drop and the individual turn radii turned out to be the main variables that determine speed and acceleration. Thus the safety of a new ice track is mainly ensured in the planning phase, in which the use of a simulation model similar to this is essential. PMID:21185562

  19. High-Density Plasma Reactors: Simulations for Design

    NASA Technical Reports Server (NTRS)

    Hash, David B.; Meyyappan, Meyya; Arnold, James O. (Technical Monitor)

    1998-01-01

    The development of improved and more efficient plasma reactors is a costly process for the semiconductor industry. Until five years ago, the Industry made most of its advancements through a trial and error approach. More recently, the role of computational modeling in the design process has increased. Both conventional computational fluid dynamics (CFD) techniques like Navier-Stokes solvers as well as particle simulation methods are used to model plasma reactor flowfields. However, since high-density plasma reactors generally operate at low gas pressures on the order of 1 to 10 mTorr, a particle simulation may be necessary because of the failure of CFD techniques to model rarefaction effects. The direct simulation Monte Carlo method is the most widely accepted and employed particle simulation tool and has previously been used to investigate plasma reactor flowfields. A plasma DSMC code is currently under development at NASA Ames Research Center with its foundation as the object-oriented parallel Cornell DSMC code, MONACO. The present investigation is a follow up of a neutral flow investigation of the effects of process parameters as well as reactor design on etch rate and etch rate uniformity. The previous work concentrated on silicon etch of a chlorine flow in a configuration typical of electron cyclotron resonance (ECR) or helical resonator type reactors. The effects of the plasma on the dissociation chemistry were modeled by making assumptions about the electron temperature and number density. The electrons or ions themselves were not simulated.The present work extends these results by simulating the charged species.The electromagnetic fields are calculated such that power deposition is modeled self-consistently. Electron impact reactions are modeled along with mechanisms for charge exchange. An bipolar diffusion assumption is made whereby electrons remain tied to the ions. However, the velocities of tile electrons are allowed to be modified during collisions

  20. Autophagic activity dictates the cellular response to oncogenic RAS

    PubMed Central

    Wang, Yihua; Wang, Xiao Dan; Lapi, Eleonora; Sullivan, Alexandra; Jia, Wei; He, You-Wen; Ratnayaka, Indrika; Zhong, Shan; Goldin, Robert D.; Goemans, Christoph G.; Tolkovsky, Aviva M.; Lu, Xin

    2012-01-01

    RAS is frequently mutated in human cancers and has opposing effects on autophagy and tumorigenesis. Identifying determinants of the cellular responses to RAS is therefore vital in cancer research. Here, we show that autophagic activity dictates the cellular response to oncogenic RAS. N-terminal Apoptosis-stimulating of p53 protein 2 (ASPP2) mediates RAS-induced senescence and inhibits autophagy. Oncogenic RAS-expressing ASPP2(Δ3/Δ3) mouse embryonic fibroblasts that escape senescence express a high level of ATG5/ATG12. Consistent with the notion that autophagy levels control the cellular response to oncogenic RAS, overexpressing ATG5, but not autophagy-deficient ATG5 mutant K130R, bypasses RAS-induced senescence, whereas ATG5 or ATG3 deficiency predisposes to it. Mechanistically, ASPP2 inhibits RAS-induced autophagy by competing with ATG16 to bind ATG5/ATG12 and preventing ATG16/ATG5/ATG12 formation. Hence, ASPP2 modulates oncogenic RAS-induced autophagic activity to dictate the cellular response to RAS: to proliferate or senesce. PMID:22847423

  1. R-Ras contributes to LTP and contextual discrimination.

    PubMed

    Darcy, M J; Jin, S-X; Feig, L A

    2014-09-26

    The ability to discriminate between closely related contexts is a specific form of hippocampal-dependent learning that may be impaired in certain neurodegenerative disorders such as Alzheimer's and Down Syndrome. However, signaling pathways regulating this form of learning are poorly understood. Previous studies have shown that the calcium-dependent exchange factor Ras-GRF1, an activator of Rac, Ras and R-Ras GTPases, is important for this form of learning and memory. Moreover, the ability to discriminate contexts was linked to the ability of Ras-GRF1 to promote high-frequency stimulation long-term potentiation (HFS-LTP) via the activation of p38 Map kinase. Here, we show that R-Ras is involved in this form of learning by using virally-delivered miRNAs targeting R-Ras into the CA1 region of the dorsal hippocampus and observing impaired contextual discrimination. Like the loss of GRF1, knockdown of R-Ras in the CA1 also impairs the induction of HFS-LTP and p38 Map kinase. Nevertheless, experiments indicate that this involvement of R-Ras in HFS-LTP that is required for contextual discrimination is independent of Ras-GRF1. Thus, R-Ras is a novel regulator of a form of hippocampal-dependent LTP as well as learning and memory that is affected in certain forms of neurodegenerative diseases. PMID:25043327

  2. Co-Simulation for Advanced Process Design and Optimization

    SciTech Connect

    Stephen E. Zitney

    2009-01-01

    Meeting the increasing demand for clean, affordable, and secure energy is arguably the most important challenge facing the world today. Fossil fuels can play a central role in a portfolio of carbon-neutral energy options provided CO{sub 2} emissions can be dramatically reduced by capturing CO{sub 2} and storing it safely and effectively. Fossil energy industry faces the challenge of meeting aggressive design goals for next-generation power plants with CCS. Process designs will involve large, highly-integrated, and multipurpose systems with advanced equipment items with complex geometries and multiphysics. APECS is enabling software to facilitate effective integration, solution, and analysis of high-fidelity process/equipment (CFD) co-simulations. APECS helps to optimize fluid flow and related phenomena that impact overall power plant performance. APECS offers many advanced capabilities including ROMs, design optimization, parallel execution, stochastic analysis, and virtual plant co-simulations. NETL and its collaborative R&D partners are using APECS to reduce the time, cost, and technical risk of developing high-efficiency, zero-emission power plants with CCS.

  3. Design and verification of a cloud field optical simulator

    NASA Technical Reports Server (NTRS)

    Davis, J. M.; Cox, S. K.; Mckee, T. B.

    1982-01-01

    A concept and an apparatus designed to investigate the reflected and transmitted distributions of light from optically thick clouds is presented. The Cloud Field Optical Simulator (CFOS) is a laboratory device which utilizes an array of incandescent lamps as a source, simulated clouds made from cotton or styrofoam as targets, and an array of silicon photodiodes as detectors. The device allows virtually any source-target-detector geometry to be examined. Similitude between real clouds and their CFOS cotton or styrofoam counterparts is established by relying on a linear relationship between optical depth and the ratio of reflected to transmitted light for a semi-infinite layer. Comparisons of principal plane radiances observed by the CFOS with Monte Carlo computations for a water cloud at 0.7 microns show excellent agreement.

  4. Design and verification of a cloud field optical simulator

    NASA Technical Reports Server (NTRS)

    Davis, J. M.; Cox, S. K.; Mckee, T. B.

    1983-01-01

    A concept and an apparatus designed to investigate the reflected and transmitted distributions of light from optically thick clouds is presented. The Cloud Field Optical Simulator (CFOS) is a laboratory device which utilizes an array of incandescent lamps as a source, simulated clouds made from cotton or styrofoam as targets, and an array of silicon photodiodes as detectors. The device allows virtually any source-target-detector geometry to be examined. Similitude between real clouds and their CFOS cotton or styrofoam counterparts is established by relying on a linear relationship between optical depth and the ratio of reflected to transmitted light for a semiinfinite layer. Comparisons of principal plane radiances observed by the CFOS with Monte Carlo computations for a water cloud at 0.7 micron show excellent agreement. Initial applications of the CFOS are discussed.

  5. Design of virtual SCADA simulation system for pressurized water reactor

    NASA Astrophysics Data System (ADS)

    Wijaksono, Umar; Abdullah, Ade Gafar; Hakim, Dadang Lukman

    2016-02-01

    The Virtual SCADA system is a software-based Human-Machine Interface that can visualize the process of a plant. This paper described the results of the virtual SCADA system design that aims to recognize the principle of the Nuclear Power Plant type Pressurized Water Reactor. This simulation uses technical data of the Nuclear Power Plant Unit Olkiluoto 3 in Finland. This device was developed using Wonderware Intouch, which is equipped with manual books for each component, animation links, alarm systems, real time and historical trending, and security system. The results showed that in general this device can demonstrate clearly the principles of energy flow and energy conversion processes in Pressurized Water Reactors. This virtual SCADA simulation system can be used as instructional media to recognize the principle of Pressurized Water Reactor.

  6. Design and simulation of uncooled microbolometer using coventorware

    NASA Astrophysics Data System (ADS)

    Arora, Suryansh; Paras, Neha; Gurjar, Anil; Narwal, Rakesh; Prasad, B.; Kumar, Dinesh

    2016-04-01

    Recently, a lot of attention has been paid to infrared imaging using uncooled microbolometer detectors, primarily because of their low cost, and wide military and civilian applications like disaster rescue, night vision, homing and tracking, ecology and weather forecasting, target acquisition, predictive inspection and maintenance, surveillance, remote temperature sensing and medical diagnostic and treatment. The present work demonstrates the design and simulation of uncooled microbolometer detector using Coventorware tool. Geometrical optimization has been done to minimize the pixel size up to 18×18 µm. Simulated values for Different parameters like Thermal conductance, Time constant and change in temperature calculated for the structure are 1.2 × 10-7W/K, 4.44ms and 3.5K.

  7. Effects of an Experiential Learning Simulation Design on Clinical Nursing Judgment Development.

    PubMed

    Chmil, Joyce Victor; Turk, Melanie; Adamson, Katie; Larew, Charles

    2015-01-01

    Simulation design should be theory based and its effect on outcomes evaluated. This study (1) applied a model of experiential learning to design a simulation experience, (2) examined how this design affected clinical nursing judgment development, and (3) described the relationship between clinical nursing judgment development and student performance when using the experiential learning design. Findings suggest that using an experiential learning simulation design results in more highly developed nursing judgment and competency in simulation performance. PMID:25763781

  8. Differential involvement of Ras-GRF1 and Ras-GRF2 in L-DOPA-induced dyskinesia

    PubMed Central

    Bido, Simone; Solari, Nicola; Indrigo, Marzia; D’Antoni, Angela; Brambilla, Riccardo; Morari, Michele; Fasano, Stefania

    2015-01-01

    Objective Recent findings have shown that pharmacogenetic manipulations of the Ras-ERK pathway provide a therapeutic means to tackle l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID). First, we investigated whether a prolonged l-DOPA treatment differentially affected ERK signaling in medium spiny neurons of the direct pathway (dMSNs) and in cholinergic aspiny interneurons (ChIs) and assessed the role of Ras-GRF1 in both subpopulations. Second, using viral-assisted technology, we probed Ras-GRF1 and Ras-GRF2 as potential targets in this pathway. We investigated how selective blockade of striatal Ras-GRF1 or Ras-GRF2 expression impacted on LID (induction, maintenance, and reversion) and its neurochemical correlates. Methods We used both Ras-GRF1 knockout mice and lentiviral vectors (LVs) delivering short-hairpin RNA sequences (shRNAs) to obtain striatum-specific gene knockdown of Ras-GRF1 and Ras-GRF2. The consequences of these genetic manipulations were evaluated in the 6-hydroxydopamine mouse model of Parkinson’s disease. Escalating doses of l-DOPA were administered and then behavioral analysis with immunohistochemical assays and in vivo microdialysis were performed. Results Ras-GRF1 was found essential in controlling ERK signaling in dMSNs, but its ablation did not prevent ERK activation in ChIs. Moreover, striatal injection of LV-shRNA/Ras-GRF1 attenuated dyskinesia development and ERK-dependent signaling, whereas LV-shRNA/Ras-GRF2 was without effect, ruling out the involvement of Ras-GRF2 in LID expression. Accordingly, Ras-GRF1 but not Ras-GRF2 striatal gene-knockdown reduced l-DOPA-induced GABA and glutamate release in the substantia nigra pars reticulata, a neurochemical correlate of dyskinesia. Finally, inactivation of Ras-GRF1 provided a prolonged anti-dyskinetic effect for up to 7 weeks and significantly attenuated symptoms in animals with established LID. Interpretation Our results suggest that Ras-GRF1 is a promising target for LID

  9. Beam Dynamics Design and Simulation in Ion Linear Accelerators (

    Energy Science and Technology Software Center (ESTSC)

    2006-08-01

    Orginally, the ray tracing code TRACK has been developed to fulfill the many special requirements for the Rare Isotope Accelerator Facility known as RIA. Since no available beam-dynamics code met all the necessary requirements, modifications to the code TRACK were introduced to allow end-to-end (from the ion souce to the production target) simulations of the RIA machine, TRACK is a general beam-dynamics code and can be applied for the design, commissioning and operation of modernmore » ion linear accelerators and beam transport systems.« less

  10. Beam Dynamics Design and Simulation in Ion Linear Accelerators (

    SciTech Connect

    Ostroumov, Peter N.; Asseev, Vladislav N.; Mustapha, and Brahim

    2006-08-01

    Orginally, the ray tracing code TRACK has been developed to fulfill the many special requirements for the Rare Isotope Accelerator Facility known as RIA. Since no available beam-dynamics code met all the necessary requirements, modifications to the code TRACK were introduced to allow end-to-end (from the ion souce to the production target) simulations of the RIA machine, TRACK is a general beam-dynamics code and can be applied for the design, commissioning and operation of modern ion linear accelerators and beam transport systems.

  11. Wedge absorber design and simulation for MICE Step IV

    SciTech Connect

    Rogers, C.T.; Snopok, P.; Coney, L.; Hanson, G.; /UC, Riverside

    2011-03-01

    In the Muon Ionization Cooling Experiment (MICE), muons are cooled by passing through material, then through RF cavities to compensate for the energy loss; which reduces the transverse emittance. It is planned to demonstrate longitudinal emittance reduction via emittance exchange in MICE by using a solid wedge absorber in Step IV. Based on the outcome of previous studies, the shape and material of the wedge were chosen. We address here further simulation efforts for the absorber of choice as well as engineering considerations in connection with the absorber support design.

  12. Design analysis tracking and data relay satellite simulation system

    NASA Technical Reports Server (NTRS)

    1974-01-01

    The design and development of the equipment necessary to simulate the S-band multiple access link between user spacecraft, the Tracking and Data Relay Satellite, and a ground control terminal are discussed. The core of the S-band multiple access concept is the use of an Adaptive Ground Implemented Phased Array. The array contains thirty channels and provides the multiplexing and demultiplexing equipment required to demonstrate the ground implemented beam forming feature. The system provided will make it possible to demonstrate the performance of a desired user and ten interfering sources attempting to pass data through the multiple access system.

  13. Design and simulation of proportional biological operational Mu-circuit.

    PubMed

    Xu, Dechang; Cai, Zhipeng; Liu, Ke; Zeng, Xiangmiao; Ouyang, Yujing; Dai, Cuihong; Hou, Aiju; Cheng, Dayou; Li, Jianzhong

    2015-03-01

    It is challenging yet desirable to quantitatively control the expression of a target gene in practice. We design a device-Proportional Biological Operational Mu-circuit (P-BOM) incorporating AND/OR gate and operational amplifier into one circuit and explore its behaviors through simulation. The results imply that will be possible to regulate input-output proportionally by manipulating the RBS of hrpR, hrpS, tetR and output gene and used in the sensing of environmental weak signals such as dioxins. PMID:25700454

  14. Overexpressed galectin-3 in pancreatic cancer induces cell proliferation and invasion by binding Ras and activating Ras signaling.

    PubMed

    Song, Shumei; Ji, Baoan; Ramachandran, Vijaya; Wang, Huamin; Hafley, Margarete; Logsdon, Craig; Bresalier, Robert S

    2012-01-01

    Pancreatic cancer (PDAC) is a lethal disease with a five-year survival of 3-5%. Mutations in K-Ras are found in nearly all cases, but K-Ras mutations alone are not sufficient for the development of PDAC. Additional factors contribute to activation of Ras signaling and lead to tumor formation. Galectin-3 (Gal-3), a multifunctional β-galactoside-binding protein, is highly expressed in PDAC. We therefore investigated the functional role of Gal-3 in pancreatic cancer progression and its relationship to Ras signaling. Expression of Gal-3 was determined by immunohistochemistry, Q-PCR and immunoblot. Functional studies were performed using pancreatic cell lines genetically engineered to express high or low levels of Gal-3. Ras activity was examined by Raf pull-down assays. Co-immunoprecipitation and immunofluorescence were used to assess protein-protein interactions. In this study, we demonstrate that Gal-3 was highly up-regulated in human tumors and in a mutant K-Ras mouse model of PDAC. Down-regulation of Gal-3 by lentivirus shRNA decreased PDAC cell proliferation and invasion in vitro and reduced tumor volume and size in an orthotopic mouse model. Gal-3 bound Ras and maintained Ras activity; down-regulation of Gal-3 decreased Ras activity as well as Ras down-stream signaling including phosphorylation of ERK and AKT and Ral A activity. Transfection of Gal-3 cDNA into PDAC cells with low-level Gal-3 augmented Ras activity and its down-stream signaling. These results suggest that Gal-3 contributes to pancreatic cancer progression, in part, by binding Ras and activating Ras signaling. Gal-3 may therefore be a potential novel target for this deadly disease. PMID:22900040

  15. VISRAD, 3-D Target Design and Radiation Simulation Code

    NASA Astrophysics Data System (ADS)

    Li, Yingjie; Macfarlane, Joseph; Golovkin, Igor

    2015-11-01

    The 3-D view factor code VISRAD is widely used in designing HEDP experiments at major laser and pulsed-power facilities, including NIF, OMEGA, OMEGA-EP, ORION, LMJ, Z, and PLX. It simulates target designs by generating a 3-D grid of surface elements, utilizing a variety of 3-D primitives and surface removal algorithms, and can be used to compute the radiation flux throughout the surface element grid by computing element-to-element view factors and solving power balance equations. Target set-up and beam pointing are facilitated by allowing users to specify positions and angular orientations using a variety of coordinates systems (e.g., that of any laser beam, target component, or diagnostic port). Analytic modeling for laser beam spatial profiles for OMEGA DPPs and NIF CPPs is used to compute laser intensity profiles throughout the grid of surface elements. We will discuss recent improvements to the software package and plans for future developments.

  16. Numerical simulations supporting the process design of ring rolling processes

    NASA Astrophysics Data System (ADS)

    Jenkouk, V.; Hirt, G.; Seitz, J.

    2013-05-01

    In conventional Finite Element Analysis (FEA) of radial-axial ring rolling (RAR) the motions of all tools are usually defined prior to simulation in the preprocessing step. However, the real process holds up to 8 degrees of freedom (DOF) that are controlled by industrial control systems according to actual sensor values and preselected control strategies. Since the histories of the motions are unknown before the experiment and are dependent on sensor data, the conventional FEA cannot represent the process before experiment. In order to enable the usage of FEA in the process design stage, this approach integrates the industrially applied control algorithms of the real process including all relevant sensors and actuators into the FE model of ring rolling. Additionally, the process design of a novel process 'the axial profiling', in which a profiled roll is used for rolling axially profiled rings, is supported by FEA. Using this approach suitable control strategies can be tested in virtual environment before processing.

  17. The renewed battle against RAS-mutant cancers.

    PubMed

    Zhang, Fuquan; Cheong, Jit Kong

    2016-05-01

    The RAS genes encode for members of a large superfamily of guanosine-5'-triphosphate (GTP)-binding proteins that control diverse intracellular signaling pathways to promote cell proliferation. Somatic mutations in the RAS oncogenes are the most common activating lesions found in human cancers. These mutations invariably result in the gain-of-function of RAS by impairing GTP hydrolysis and are frequently associated with poor responses to standard cancer therapies. In this review, we summarize key findings of past and present landmark studies that have deepened our understanding of the RAS biology in the context of oncogenesis. We also discuss how emerging areas of research could further bolster a renewed global effort to target the largely undruggable oncogenic RAS and/or its activated downstream effector signaling cascades to achieve better treatment outcomes for RAS-mutant cancer patients. PMID:26892781

  18. An Innovative Ski-Boot: Design, Numerical Simulations and Testing

    PubMed Central

    Corazza, Stefano; Cobelli, Claudio

    2005-01-01

    The present work is concerned with the design of an innovative ski-boot. In order to optimize ergonomics and biomechanical behavior of the ski-boot it is important to take into account the orientation of the leg with respect to the ground. The SGS system (Stance Geometry System) developed in this work allows the skier to adjust for posture in the frontal plane by rotating the sole of the boot about the antero-posterior axis (ski-boot is then locked in the desired position before skiing). A simplified model of the effect of ski-boot deformation on skiing behavior is used to evaluate the minimal stiffness the system must have. An experimental analysis on the ski slopes was carried out to provide ski-boot deformations and loading data in different skiing conditions, to be used in numerical simulations. Finite Elements Method (FEM) simulations were performed for optimal design of the joint between ski-boot and sole. The active loads and local ski-boot deformations during small- and large-radius turns were experimentally determined and used to validate a FEM model of the ski-boot. The model was used to optimize the design for maximum stiffness and to demonstrate the efficacy of virtual design supported by proper experimental data. Mean loads up to 164% body weight were measured on the outer ski during turning. The new SGS design system allows the adjustment of lateral stance before using the ski-boot, optimizing the ski-boot stiffness through FEM analysis. Innovative aspects of this work included not only the stance geometry system ski-boot but also the setup of a virtual design environment that was validated by experimental evidence. An entire dataset describing loads during skiing has been obtained. The optimized SGS ski-boot increases intrinsic knee stability due to proper adjustment of lateral stance, guaranteeing appropriate stiffness of the ski-boot system. Key Points Load acting during different phases of active skiing have been investigated in both qualitative

  19. Dimerize RACK1 upon transformation with oncogenic ras

    SciTech Connect

    Chu, L.-Y.; Chen, Y.-H.; Chuang, N.-N. . E-mail: zonnc@sinica.edu.tw

    2005-05-06

    From our previous studies, we learned that syndecan-2/p120-GAP complex provided docking site for Src to prosecute tyrosine kinase activity upon transformation with oncogenic ras. And, RACK1 protein was reactive with syndecan-2 to keep Src inactivated, but not when Ras was overexpressed. In the present study, we characterized the reaction between RACK1 protein and Ras. RACK1 was isolated from BALB/3T3 cells transfected with plasmids pcDNA3.1-[S-ras(Q{sub 61}K)] of shrimp Penaeus japonicus and RACK1 was revealed to react with GTP-K{sub B}-Ras(Q{sub 61}K), not GDP-K{sub B}-Ras(Q{sub 61}K). This selective interaction between RACK1 and GTP-K{sub B}-Ras(Q{sub 61}K) was further confirmed with RACK1 of human placenta and mouse RACK1-encoded fusion protein. We found that RACK1 was dimerized upon reaction with GTP-K{sub B}-Ras(Q{sub 61}K), as well as with 14-3-3{beta} and geranylgeranyl pyrophosphate, as revealed by phosphorylation with Src tyrosine kinase. We reported the complex of RACK1/GTP-K{sub B}-Ras(Q{sub 61}K) reacted selectively with p120-GAP. This interaction was sufficient to dissemble RACK1 into monomers, a preferred form to compete for the binding of syndecan-2. These data indicate that the reaction of GTP-K{sub B}-Ras(Q{sub 61}K) with RACK1 in dimers may operate a mechanism to deplete RACK1 from reaction with syndecan-2 upon transformation by oncogenic ras and the RACK1/GTP-Ras complex may provide a route to react with p120-GAP and recycle monomeric RACK1 to syndecan-2.

  20. Characterization of the Ras homologue of Schistosoma mansoni.

    PubMed

    Osman, A; Niles, E G; LoVerde, P T

    1999-05-15

    Ras is a member of a super-family of guanine-binding or G-proteins. Ras functions as a molecular switch in the transduction of signals generated by the activation of a variety of cell surface receptors and relays the signals to downstream effectors. Little is known about signal transduction in schistosomes. In order for Schistosoma mansoni to survive different immune responses triggered by the host as well as to migrate from the site of penetration at the skin to the final destination in portal circulation, they must receive signals from the host environment and respond to them in a way that allows their survival. We have isolated the schistosome Ras cDNA by using sequence information of the schistosome Ras homologue submitted to the Genbank database. Analysis of the encoded peptide revealed 81% identity and 92% similarity with K-Ras from various species. Ras is a single copy gene as determined by quantitative hybridization experiments. The cDNA was cloned into pGEX-4T and the expressed peptide was used to generate specific antibody reagents. Affinity purified antibodies identified a 23 kDa native protein that localizes to the subtegument. Ras is not associated with the tegument. Ras is expressed in all the developmental stages of the parasite. However, Ras is over-expressed in female worms compared to males. Schistosome Ras was also shown to be post-translationally modified by addition of farnesyl isoprenoid moiety to the cysteine residue in the C-terminal box. Using a schistosome extract in vitro SmRas farnesylation was inhibited by the farnesyl transferase inhibitor, FTI-277, at concentrations comparable to those required to inhibit K-Ras processing. These initial studies on signal transduction in schistosomes should provide a solid basis for improving our understanding of schistosome-host interactions. PMID:10376991

  1. Simulation of Wind Profile Perturbations for Launch Vehicle Design

    NASA Technical Reports Server (NTRS)

    Adelfang, S. I.

    2004-01-01

    Ideally, a statistically representative sample of measured high-resolution wind profiles with wavelengths as small as tens of meters is required in design studies to establish aerodynamic load indicator dispersions and vehicle control system capability. At most potential launch sites, high- resolution wind profiles may not exist. Representative samples of Rawinsonde wind profiles to altitudes of 30 km are more likely to be available from the extensive network of measurement sites established for routine sampling in support of weather observing and forecasting activity. Such a sample, large enough to be statistically representative of relatively large wavelength perturbations, would be inadequate for launch vehicle design assessments because the Rawinsonde system accurately measures wind perturbations with wavelengths no smaller than 2000 m (1000 m altitude increment). The Kennedy Space Center (KSC) Jimsphere wind profiles (150/month and seasonal 2 and 3.5-hr pairs) are the only adequate samples of high resolution profiles approx. 150 to 300 m effective resolution, but over-sampled at 25 m intervals) that have been used extensively for launch vehicle design assessments. Therefore, a simulation process has been developed for enhancement of measured low-resolution Rawinsonde profiles that would be applicable in preliminary launch vehicle design studies at launch sites other than KSC.

  2. Integrating Multibody Simulation and CFD: toward Complex Multidisciplinary Design Optimization

    NASA Astrophysics Data System (ADS)

    Pieri, Stefano; Poloni, Carlo; Mühlmeier, Martin

    This paper describes the use of integrated multidisciplinary analysis and optimization of a race car model on a predefined circuit. The objective is the definition of the most efficient geometric configuration that can guarantee the lowest lap time. In order to carry out this study it has been necessary to interface the design optimization software modeFRONTIER with the following softwares: CATIA v5, a three dimensional CAD software, used for the definition of the parametric geometry; A.D.A.M.S./Motorsport, a multi-body dynamic simulation software; IcemCFD, a mesh generator, for the automatic generation of the CFD grid; CFX, a Navier-Stokes code, for the fluid-dynamic forces prediction. The process integration gives the possibility to compute, for each geometrical configuration, a set of aerodynamic coefficients that are then used in the multiboby simulation for the computation of the lap time. Finally an automatic optimization procedure is started and the lap-time minimized. The whole process is executed on a Linux cluster running CFD simulations in parallel.

  3. A design of camera simulator for photoelectric image acquisition system

    NASA Astrophysics Data System (ADS)

    Cai, Guanghui; Liu, Wen; Zhang, Xin

    2015-02-01

    In the process of developing the photoelectric image acquisition equipment, it needs to verify the function and performance. In order to make the photoelectric device recall the image data formerly in the process of debugging and testing, a design scheme of the camera simulator is presented. In this system, with FPGA as the control core, the image data is saved in NAND flash trough USB2.0 bus. Due to the access rate of the NAND, flash is too slow to meet the requirement of the sytsem, to fix the problem, the pipeline technique and the High-Band-Buses technique are applied in the design to improve the storage rate. It reads image data out from flash in the control logic of FPGA and output separately from three different interface of Camera Link, LVDS and PAL, which can provide image data for photoelectric image acquisition equipment's debugging and algorithm validation. However, because the standard of PAL image resolution is 720*576, the resolution is different between PAL image and input image, so the image can be output after the resolution conversion. The experimental results demonstrate that the camera simulator outputs three format image sequence correctly, which can be captured and displayed by frame gather. And the three-format image data can meet test requirements of the most equipment, shorten debugging time and improve the test efficiency.

  4. MK2 Regulates Ras Oncogenesis through Stimulating ROS Production

    PubMed Central

    Kobayashi, Yusuke; Qi, Xiaomei

    2012-01-01

    Ras signals through both mitogenic and stress pathways and studies of Ras regulatory effects of stress pathways hold great promise to control Ras-dependent malignancies. Our previous work showed Ras activation of a stress kinase (MAPK-activated protein kinase 2 [MK2]), and here, we examine regulatory effects of MK2 on Ras oncogenesis. MK2 knockout was shown to increase Ras transformation in mouse embryonic fibroblasts (MEFs) in vitro and to enhance the resultant tumor growth in mice, indicating a tumor suppressor activity. In Ras-dependent and -independent human colon cancer, however, MK2-forced expression increases and MK2 depletion decreases the malignant growth, suggesting its oncogenic activity. The oncogenic activity of MK2 couples with its activation by both stress and mitogenic signals through extracellular signal–regulated kinase and p38α pathways, whereas its tumor-suppressing effect links to its stimulation only by stress downstream of p38α. Of interest, MK2 was shown to decrease intracellular levels of reactive oxygen species (ROS) in MEFs but increase its production in human colon cancer cells, and experiments with antioxidants revealed that ROS is required for Ras oncogenesis in both systems. These results indicate that MK2 can increase or decrease Ras oncogenesis dependent of its ROS regulatory activities. PMID:23264852

  5. Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator.

    PubMed Central

    Hofer, F; Fields, S; Schneider, C; Martin, G S

    1994-01-01

    The yeast two-hybrid system was used to identify proteins that interact with Ras. The H-Ras protein was found to interact with a guanine nucleotide dissociation stimulator (GDS) that has been previously shown to regulate guanine nucleotide exchange on another member of the Ras protein family, Ral. The interaction is mediated by the C-terminal, noncatalytic segment of the RalGDS and can be detected both in vivo, using the two-hybrid system, and in vitro, with purified recombinant proteins. The interaction of the RalGDS C-terminal segment with Ras is specific, dependent on activation of Ras by GTP, and blocked by a mutation that affects Ras effector function. These characteristics are similar to those previously demonstrated for the interaction between Ras and its putative effector, Raf, suggesting that the RalGDS may also be a Ras effector. Consistent with this idea, the RalGDS was found to inhibit the binding of Raf to Ras. Images PMID:7972015

  6. Interaction of Ras with phosphoinositide 3-kinase gamma.

    PubMed Central

    Rubio, I; Rodriguez-Viciana, P; Downward, J; Wetzker, R

    1997-01-01

    Phosphoinositide 3-kinase gamma (PI3Kgamma) can be activated in vitro by both alpha and betagamma subunits of heterotrimeric G-proteins and does not interact with p85, the regulatory subunit of PI3Kalpha. Here we demonstrate the binding of Ras to PI3Kgamma in vitro. An N-terminal region of PI3Kgamma was identified as a binding site for Ras. After co-expression with PI3Kgamma in COS-7 cells, Ras induced only a modest increase in PI3K activity compared with the stimulation of PI3Kalpha by Ras in the same cells. PMID:9307042

  7. RAS isoforms and mutations in cancer at a glance.

    PubMed

    Hobbs, G Aaron; Der, Channing J; Rossman, Kent L

    2016-04-01

    RAS proteins (KRAS4A, KRAS4B, NRAS and HRAS) function as GDP-GTP-regulated binary on-off switches, which regulate cytoplasmic signaling networks that control diverse normal cellular processes. Gain-of-function missense mutations in RAS genes are found in ∼25% of human cancers, prompting interest in identifying anti-RAS therapeutic strategies for cancer treatment. However, despite more than three decades of intense effort, no anti-RAS therapies have reached clinical application. Contributing to this failure has been an underestimation of the complexities of RAS. First, there is now appreciation that the four human RAS proteins are not functionally identical. Second, with >130 different missense mutations found in cancer, there is an emerging view that there are mutation-specific consequences on RAS structure, biochemistry and biology, and mutation-selective therapeutic strategies are needed. In this Cell Science at a Glance article and accompanying poster, we provide a snapshot of the differences between RAS isoforms and mutations, as well as the current status of anti-RAS drug-discovery efforts. PMID:26985062

  8. Activation of ras oncogenes preceding the onset of neoplasia

    SciTech Connect

    Kumar, R.; Barbacid, M. ); Sukumar, S. )

    1990-06-01

    The identification of ras oncogenes in human and animal cancers including precancerous lesions indicates that these genes participate in the early stages of neoplastic development. Yet, these observations do not define the timing of ras oncogene activation in the multistep process of carcinogenesis. To ascertain the timing of ras oncogene activation, an animal model system was devised that involves the induction of mammary carcinomas in rats exposed at birth to the carcinogen nitrosomethylurea. High-resolution restriction fragment length polymorphism analysis of polymerase chain reaction-amplified ras sequences revealed the presence of both H-ras and K-ras oncogenes in normal mammary glands 2 weeks after carcinogen treatment and at least 2 months before the onset of neoplasia. These ras oncogenes can remain latent within the mammary gland until exposure to estrogens, demonstrating that activation of ras oncogenes can precede the onset of neoplasia and suggesting that normal physiological proliferative processes such as estrogen-induced mammary gland development may lead to neoplasia if the targeted cells harbor latent ras oncogenes.

  9. Simulation-aided design and synthesis of hierarchically porous membranes.

    PubMed

    Li, Fan; Wilker, Molly B; Stein, Andreas

    2012-05-15

    Free-standing silica membranes with hierarchical porosity (ca. 300 nm macropores surrounded by 6-8 nm mesopores) and controllable mesopore architecture were prepared by a dual-templating method, with the structural design aided by mesoscale simulation. To create a two-dimensional, hexagonal macropore array, polymeric colloidal hemisphere arrays were synthesized by a two-step annealing process starting with non-close-packed polystyrene sphere arrays on silicon coated with a sacrificial alumina layer. A silica precursor containing a poly(ethylene) oxide-poly(propylene oxide)-poly(ethylene) oxide (PEO-PPO-PEO) triblock-copolymer surfactant as template for mesopore creation was spin-coated onto the support and aged and then converted into the free-standing membranes by dissolving both templates and the alumina layer. To test the hypothesis that the mesopore architecture may be influenced by confinement of the surfactant-containing precursor solution in the colloidal array and by its interactions with the polymeric colloids, the system was studied theoretically by dissipative particle dynamics (DPD) simulations and experimentally by examining the pore structures of silica membranes via electron microscopy. The DPD simulations demonstrated that, while only tilted columnar structure can be formed through tuning the interaction with the substrate, perfect alignment of 2D hexagonal micelles perpendicular to the plane of the membrane is achievable by confinement between parallel walls that interact preferentially with the hydrophilic components (PEO blocks, silicate, and solvent). The simulations predicted that this alignment could be maintained across a span of up to 10 columns of micelles, the same length scale defined by the colloidal array. In the actual membranes, we manipulated the mesopore alignment by tuning the solvent polarity relative to the polar surface characteristics of the colloidal hemispheres. With methanol as a solvent, columnar mesopores parallel to the

  10. The Use of Piloted Simulation for Civil Tiltrotor Integrated Cockpit Design

    NASA Technical Reports Server (NTRS)

    Decker, William A.; Simmons, Rickey C.; Tucker, George E.

    1996-01-01

    Ground-based flight simulators are receiving increased use in the design of civil aircraft. In addition to traditional simulation roles in support of cockpit control and display design, simulators are now used to develop new flight procedures and to assist in airport design. This is particularly true for the concept of a civil tiltrotor transport. This presentation summarizes recent simulation activity at NASA's Ames Research Center focused on the design requirements for the introduction of tiltrotor aircraft as economic vertical flight transports.

  11. Functional requirements for design of the Space Ultrareliable Modular Computer (SUMC) system simulator

    NASA Technical Reports Server (NTRS)

    Curran, R. T.; Hornfeck, W. A.

    1972-01-01

    The functional requirements for the design of an interpretive simulator for the space ultrareliable modular computer (SUMC) are presented. A review of applicable existing computer simulations is included along with constraints on the SUMC simulator functional design. Input requirements, output requirements, and language requirements for the simulator are discussed in terms of a SUMC configuration which may vary according to the application.

  12. Variational data assimilation system "INM RAS - Black Sea"

    NASA Astrophysics Data System (ADS)

    Parmuzin, Eugene; Agoshkov, Valery; Assovskiy, Maksim; Giniatulin, Sergey; Zakharova, Natalia; Kuimov, Grigory; Fomin, Vladimir

    2013-04-01

    Development of Informational-Computational Systems (ICS) for Data Assimilation Procedures is one of multidisciplinary problems. To study and solve these problems one needs to apply modern results from different disciplines and recent developments in: mathematical modeling; theory of adjoint equations and optimal control; inverse problems; numerical methods theory; numerical algebra and scientific computing. The problems discussed above are studied in the Institute of Numerical Mathematics of the Russian Academy of Science (INM RAS) in ICS for Personal Computers (PC). Special problems and questions arise while effective ICS versions for PC are being developed. These problems and questions can be solved with applying modern methods of numerical mathematics and by solving "parallelism problem" using OpenMP technology and special linear algebra packages. In this work the results on the ICS development for PC-ICS "INM RAS - Black Sea" are presented. In the work the following problems and questions are discussed: practical problems that can be studied by ICS; parallelism problems and their solutions with applying of OpenMP technology and the linear algebra packages used in ICS "INM - Black Sea"; Interface of ICS. The results of ICS "INM RAS - Black Sea" testing are presented. Efficiency of technologies and methods applied are discussed. The work was supported by RFBR, grants No. 13-01-00753, 13-05-00715 and by The Ministry of education and science of Russian Federation, project 8291, project 11.519.11.1005 References: [1] V.I. Agoshkov, M.V. Assovskii, S.A. Lebedev, Numerical simulation of Black Sea hydrothermodynamics taking into account tide-forming forces. Russ. J. Numer. Anal. Math. Modelling (2012) 27, No.1, 5-31 [2] E.I. Parmuzin, V.I. Agoshkov, Numerical solution of the variational assimilation problem for sea surface temperature in the model of the Black Sea dynamics. Russ. J. Numer. Anal. Math. Modelling (2012) 27, No.1, 69-94 [3] V.B. Zalesny, N.A. Diansky, V

  13. Application of Simulated Annealing and Related Algorithms to TWTA Design

    NASA Technical Reports Server (NTRS)

    Radke, Eric M.

    2004-01-01

    Simulated Annealing (SA) is a stochastic optimization algorithm used to search for global minima in complex design surfaces where exhaustive searches are not computationally feasible. The algorithm is derived by simulating the annealing process, whereby a solid is heated to a liquid state and then cooled slowly to reach thermodynamic equilibrium at each temperature. The idea is that atoms in the solid continually bond and re-bond at various quantum energy levels, and with sufficient cooling time they will rearrange at the minimum energy state to form a perfect crystal. The distribution of energy levels is given by the Boltzmann distribution: as temperature drops, the probability of the presence of high-energy bonds decreases. In searching for an optimal design, local minima and discontinuities are often present in a design surface. SA presents a distinct advantage over other optimization algorithms in its ability to escape from these local minima. Just as high-energy atomic configurations are visited in the actual annealing process in order to eventually reach the minimum energy state, in SA highly non-optimal configurations are visited in order to find otherwise inaccessible global minima. The SA algorithm produces a Markov chain of points in the design space at each temperature, with a monotonically decreasing temperature. A random point is started upon, and the objective function is evaluated at that point. A stochastic perturbation is then made to the parameters of the point to arrive at a proposed new point in the design space, at which the objection function is evaluated as well. If the change in objective function values (Delta)E is negative, the proposed new point is accepted. If (Delta)E is positive, the proposed new point is accepted according to the Metropolis criterion: rho((Delta)f) = exp((-Delta)E/T), where T is the temperature for the current Markov chain. The process then repeats for the remainder of the Markov chain, after which the temperature is

  14. The IAA RAS Correlator First Results

    NASA Technical Reports Server (NTRS)

    Surkis, Igor; Melnikov, Alexey; Shantyr, Violet; Zimovsky, Vladimir

    2010-01-01

    In 2009 the national Russian VLBI observations were processed by the new correlator ARC (Astrometric Radiointerferometric Correlator). The ARC is a VSI-H correlator and equipped with Mark 5B playback terminals. During 2009 ARC was used to process a series of VLBI sessions, observed on stations Svetloe, Zelenchukskaya, and Badary. NGS files were formed, and EOP parameters were obtained by IAA RAS Analysis Center. The accuracies of the pole coordinates and UT1-UTC were 1-2 mas and 0.07-0.1 ms, respectively.

  15. Small molecule binding sites on the Ras:SOS complex can be exploited for inhibition of Ras activation.

    PubMed

    Winter, Jon J G; Anderson, Malcolm; Blades, Kevin; Brassington, Claire; Breeze, Alexander L; Chresta, Christine; Embrey, Kevin; Fairley, Gary; Faulder, Paul; Finlay, M Raymond V; Kettle, Jason G; Nowak, Thorsten; Overman, Ross; Patel, S Joe; Perkins, Paula; Spadola, Loredana; Tart, Jonathan; Tucker, Julie A; Wrigley, Gail

    2015-03-12

    Constitutively active mutant KRas displays a reduced rate of GTP hydrolysis via both intrinsic and GTPase-activating protein-catalyzed mechanisms, resulting in the perpetual activation of Ras pathways. We describe a fragment screening campaign using X-ray crystallography that led to the discovery of three fragment binding sites on the Ras:SOS complex. The identification of tool compounds binding at each of these sites allowed exploration of two new approaches to Ras pathway inhibition by stabilizing or covalently modifying the Ras:SOS complex to prevent the reloading of Ras with GTP. Initially, we identified ligands that bound reversibly to the Ras:SOS complex in two distinct sites, but these compounds were not sufficiently potent inhibitors to validate our stabilization hypothesis. We conclude by demonstrating that covalent modification of Cys118 on Ras leads to a novel mechanism of inhibition of the SOS-mediated interaction between Ras and Raf and is effective at inhibiting the exchange of labeled GDP in both mutant (G12C and G12V) and wild type Ras. PMID:25695162

  16. RasGRP1 opposes proliferative EGFR–SOS1–Ras signals and restricts intestinal epithelial cell growth

    PubMed Central

    Depeille, Philippe; Henricks, Linda M.; van de Ven, Robert A. H.; Lemmens, Ed; Wang, Chih-Yang; Matli, Mary; Werb, Zena; Haigis, Kevin M.; Donner, David; Warren, Robert; Roose, Jeroen P.

    2015-01-01

    The character of EGFR signals can influence cell fate but mechanistic insights into intestinal EGFR-Ras signalling are limited. Here we show that two distinct Ras nucleotide exchange factors, RasGRP1 and SOS1, lie downstream of EGFR but act in functional opposition. RasGRP1 is expressed in intestinal crypts where it restricts epithelial growth. High RasGRP1 expression in colorectal cancer (CRC) patient samples correlates with a better clinical outcome. Biochemically, we find that RasGRP1 creates a negative feedback loop that limits proliferative EGFR–SOS1–Ras signals in CRC cells. Genetic Rasgrp1 depletion from mice with either an activating mutation in KRas or with aberrant Wnt signalling due to a mutation in Apc resulted in both cases in exacerbated Ras–ERK signalling and cell proliferation. The unexpected opposing cell biological effects of EGFR–RasGRP1 and EGFR–SOS1 signals in the same cell shed light on the intricacy of EGFR-Ras signalling in normal epithelium and carcinoma. PMID:26005835

  17. RasGRP1 overexpression in T-ALL increases basal nucleotide exchange on Ras rendering the Ras/PI3K/Akt pathway responsive to protumorigenic cytokines.

    PubMed

    Ksionda, O; Melton, A A; Bache, J; Tenhagen, M; Bakker, J; Harvey, R; Winter, S S; Rubio, I; Roose, J P

    2016-07-14

    Ras GTPases are activated by RasGEFs and inactivated by RasGAPs, which stimulate the hydrolysis of RasGTP to inactive RasGDP. GTPase-impairing somatic mutations in RAS genes, such as KRAS(G12D), are among the most common oncogenic events in metastatic cancer. A different type of cancer Ras signal, driven by overexpression of the RasGEF RasGRP1 (Ras guanine nucleotide-releasing protein 1), was recently implicated in pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients and murine models, in which RasGRP1 T-ALLs expand in response to treatment with interleukins (ILs) 2, 7 and 9. Here, we demonstrate that IL-2/7/9 stimulation activates Erk and Akt pathways downstream of Ras in RasGRP1 T-ALL but not in normal thymocytes. In normal lymphocytes, RasGRP1 is recruited to the membrane by diacylglycerol (DAG) in a phospholipase C-γ (PLCγ)-dependent manner. Surprisingly, we find that leukemic RasGRP1-triggered Ras-Akt signals do not depend on acute activation of PLCγ to generate DAG but rely on baseline DAG levels instead. In agreement, using three distinct assays that measure different aspects of the RasGTP/GDP cycle, we established that overexpression of RasGRP1 in T-ALLs results in a constitutively high GTP-loading rate of Ras, which is constantly counterbalanced by hydrolysis of RasGTP. KRAS(G12D) T-ALLs do not show constitutive GTP loading of Ras. Thus, we reveal an entirely novel type of leukemogenic Ras signals that is based on a RasGRP1-driven increased in flux through the RasGTP/GDP cycle, which is mechanistically very different from KRAS(G12D) signals. Our studies highlight the dynamic balance between RasGEF and RasGAP in these T-ALLs and put forth a new model in which IL-2/7/9 decrease RasGAP activity. PMID:26549032

  18. Society News: Why become a Fellow of the Society? The 2010 RAS Fellowships; Using the RAS Library; Think grants! New Fellows

    NASA Astrophysics Data System (ADS)

    2011-04-01

    There are many arguments for joining the Society - supporting the RAS in lobbying, funding research and holding meetings, for example - but don't forget that benefits also come to individual Fellows. The RAS is pleased to announce the award of three RAS Fellowships in addition to the RAS Sir Norman Lockyer Fellowship.

  19. Simulation Assisted Risk Assessment Applied to Launch Vehicle Conceptual Design

    NASA Technical Reports Server (NTRS)

    Mathias, Donovan L.; Go, Susie; Gee, Ken; Lawrence, Scott

    2008-01-01

    A simulation-based risk assessment approach is presented and is applied to the analysis of abort during the ascent phase of a space exploration mission. The approach utilizes groupings of launch vehicle failures, referred to as failure bins, which are mapped to corresponding failure environments. Physical models are used to characterize the failure environments in terms of the risk due to blast overpressure, resulting debris field, and the thermal radiation due to a fireball. The resulting risk to the crew is dynamically modeled by combining the likelihood of each failure, the severity of the failure environments as a function of initiator and time of the failure, the robustness of the crew module, and the warning time available due to early detection. The approach is shown to support the launch vehicle design process by characterizing the risk drivers and identifying regions where failure detection would significantly reduce the risk to the crew.

  20. Colossal Tooling Design: 3D Simulation for Ergonomic Analysis

    NASA Technical Reports Server (NTRS)

    Hunter, Steve L.; Dischinger, Charles; Thomas, Robert E.; Babai, Majid

    2003-01-01

    The application of high-level 3D simulation software to the design phase of colossal mandrel tooling for composite aerospace fuel tanks was accomplished to discover and resolve safety and human engineering problems. The analyses were conducted to determine safety, ergonomic and human engineering aspects of the disassembly process of the fuel tank composite shell mandrel. Three-dimensional graphics high-level software, incorporating various ergonomic analysis algorithms, was utilized to determine if the process was within safety and health boundaries for the workers carrying out these tasks. In addition, the graphical software was extremely helpful in the identification of material handling equipment and devices for the mandrel tooling assembly/disassembly process.

  1. Numerical simulation for the high performance industrial reheating furnace design

    SciTech Connect

    Murakami, Hideki; Saito, Toshiaki; Hayashi, Junnichi; Hida, Atsushi

    1999-07-01

    The high performance industrial furnace, providing significant energy savings, low pollutant emission and high control ability on heating, has been developing. For designing the process, numerical simulations of a slab reheating furnace, with the advanced combustion system adopting highly preheated air have been performed, using a three-dimensional unsteady mathematical model. An essential feature of the model is the incorporation of the three-dimensional turbulent model (LES) and the Radiative Energy Absorption Distribution (READ) method. Numerical results has been verified with experimental results, velocity data of a water-model and heat flux data of a large unit furnace. The results have been, also, visualized by the thermal particle method. The numerical results lead to the conclusion that the regenerative burner system developed has the large advantage of heating slabs uniformly in a wide reheating furnace, and suggest possibility of a compact reheating furnace.

  2. The design and simulation test of wireless antenna protection network

    NASA Astrophysics Data System (ADS)

    Chen, Zipeng; Dai, Yawen; Li, Peng; Li, Zhuoqiu

    2013-03-01

    In this paper, a wireless antenna protection program has been designed. In the program, the TVS diode was used as the first lever for protection, and the π-type high pass filtering network as the second lever. As a result, the program not only has the traditional function of ESD protection, which can avoid the high voltage damage to the internal circuit, but also achieves the purpose of load matching, ensuring the signal source not to distort. The ADS simulation software was used to test the ability of this program for filtering and impedance matching, which proved the feasibility of this program. The wireless antenna protection network has been practically used, and its' performance of anti-electromagnetic interference has been validated.

  3. Designing Crop Simulation Web Service with Service Oriented Architecture Principle

    NASA Astrophysics Data System (ADS)

    Chinnachodteeranun, R.; Hung, N. D.; Honda, K.

    2015-12-01

    Crop simulation models are efficient tools for simulating crop growth processes and yield. Running crop models requires data from various sources as well as time-consuming data processing, such as data quality checking and data formatting, before those data can be inputted to the model. It makes the use of crop modeling limited only to crop modelers. We aim to make running crop models convenient for various users so that the utilization of crop models will be expanded, which will directly improve agricultural applications. As the first step, we had developed a prototype that runs DSSAT on Web called as Tomorrow's Rice (v. 1). It predicts rice yields based on a planting date, rice's variety and soil characteristics using DSSAT crop model. A user only needs to select a planting location on the Web GUI then the system queried historical weather data from available sources and expected yield is returned. Currently, we are working on weather data connection via Sensor Observation Service (SOS) interface defined by Open Geospatial Consortium (OGC). Weather data can be automatically connected to a weather generator for generating weather scenarios for running the crop model. In order to expand these services further, we are designing a web service framework consisting of layers of web services to support compositions and executions for running crop simulations. This framework allows a third party application to call and cascade each service as it needs for data preparation and running DSSAT model using a dynamic web service mechanism. The framework has a module to manage data format conversion, which means users do not need to spend their time curating the data inputs. Dynamic linking of data sources and services are implemented using the Service Component Architecture (SCA). This agriculture web service platform demonstrates interoperability of weather data using SOS interface, convenient connections between weather data sources and weather generator, and connecting

  4. Conceptual Design and Simulation of Forced Convection Micro Heat Spreaders

    NASA Astrophysics Data System (ADS)

    Sert, Cuneyt; Warburton, Tim; Beskok, Ali

    1999-11-01

    The micro heat spreader (MHS) is a closed loop single-phase microfluidic system for efficient dissipation of large, concentrated heat loads. The MHS connects two flow expansion chambers through a micro-channel. The bottom surfaces of the expansion chambers consist of electrostatically actuated micro-membranes. A continuous pumping action for the coolant fluid is generated by driving the membranes with a phase difference of π. Heat generated by the source located just above the micro-channel is rapidly conducted to the fluid due to the small micro-channel height. While the hot fluid is pumped towards the exit of the micro-channel, sudden expansion of the geometry in to the mixing chamber promotes flow separation and mixing of the exiting hot fluid with the colder fluid in the chamber. The pumping direction then reverses, and the procedure is repeated cyclically. The concept testing of the MHS is obtained by an h/p finite element simulation package Nektar, based on an arbitrary Lagrangian Eulerian formulation for solution of the Navier-Stokes and the heat transport equations. The simulations performed for water at Re=6 indicated a thermal energy removal rate of 60 W/cm^2, with a maximum temperature difference of 10 K on the MHS surface. This heat flux is an order of magnitude higher than that dissipated by the micro-heat-pipes used in electronic cooling. The proposed microfluidic design also allows closed-loop control strategies for efficient dissipation of time varying thermal loads.

  5. K-Ras promotes the non-small lung cancer cells survival by cooperating with sirtuin 1 and p27 under ROS stimulation.

    PubMed

    Cheng, Dezhi; Zhao, Liang; Xu, Yunsheng; Ou, Rongying; Li, Gang; Yang, Han; Li, Wenfeng

    2015-09-01

    Cigarette smoking might lead to lung cancer. However, the related signaling pathways at molecular level remained unknown until now. In this study, we studied the signaling processes associated between tobacco exposure and lung cancer. First, we detected and validated pathway-specific gene expression at bronchial epithelium. These proteins reflected the activation of signaling pathways relevant to tobacco exposure, including ATM, BCL2, GPX1, K-Ras, IKBKB, and SIRT1. Tobacco smoking was simulated via reactive oxygen species (ROS) pathway. ROS not only arrested cell cycle at G1/S stage but also increased expressions of Sirt1 and p27. Further studies showed that the expression of p27 was dependent on ERK1/2 activation, and p27 itself could halt cell cycle by inhibiting the activation of CDKs. Moreover, activation of K-Ras, the key regulator of Ras/ERK pathway, was tightly regulated by enzyme activity of Sirt1. Deacetylation of K-Ras by Sirt1 increased the transformation of Ras-GTP to Ras-GDP, promoting the activation of downstream of ERK1/2. In reverse, Ras/ERK pathway could also regulate Sirt1 transcription. In conclusion, inhibition of Sirt1 may be an effective strategy for the prevention of tumor progression in high-risk patients or as a therapeutic strategy in established tumors. PMID:25894374

  6. H-Ras regulation of TRAIL death receptor mediated apoptosis

    PubMed Central

    Chen, Jun-Jie; Bozza, William P.; Di, Xu; Zhang, Yaqin; Hallett, William; Zhang, Baolin

    2014-01-01

    TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis through the death receptors (DRs) 4 and/or 5 expressed on the cell surface. Multiple clinical trials are underway to evaluate the antitumor activity of recombinant human TRAIL and agonistic antibodies to DR4 or DR5. However, their therapeutic potential is limited by the high frequency of cancer resistance. Here we provide evidence demonstrating the role of H-Ras in TRAIL receptor mediated apoptosis. By analyzing the genome wide mRNA expression data of the NCI60 cancer cell lines, we found that H-Ras expression was consistently upregulated in TRAIL-resistant cell lines. By contrast, no correlation was found between TRAIL sensitivity and K-Ras expression levels or their mutational profiles. Notably, H-Ras upregulation associated with a surface deficiency of TRAIL death receptors. Selective inhibition of H-Ras activity in TRAIL-resistant cells restored the surface expression of both DR4 and DR5 without changing their total protein levels. The resulting cells became highly susceptible to both TRAIL and agonistic DR5 antibody, whereas K-Ras inhibition had little or no effect on TRAIL-induced apoptosis, indicating H-Ras plays a distinct role in the regulation of TRAIL death receptors. Further studies are warranted to determine the therapeutic potential of H-Ras-specific inhibitors in combination with TRAIL receptor agonists. PMID:25026275

  7. Ras and autophagy in cancer development and therapy

    PubMed Central

    Schmukler, Eran; Kloog, Yoel; Pinkas-Kramarski, Ronit

    2014-01-01

    Autophagy, a process of self-degradation and turnover of cellular components, plays a complex role in cancer. Evidence exists to show that autophagy may support tumor growth and cell survival, whereas it can also contribute to tumor suppression and have anti-survival characteristics in different cellular systems. Numerous studies have described the effects of various oncogenes and tumor suppressors on autophagy. The small GTPase Ras is an oncogene involved in the regulation of various cell-signaling pathways, and is mutated in 33% of human cancers. In the present review, we discuss the interplay between Ras and autophagy in relation to oncogenesis. It appears that Ras can upregulate or downregulate autophagy through several signaling pathways. In turn, autophagy can affect the tumorigenicity driven by Ras, resulting in either tumor progression or repression, depending on the cellular context. Furthermore, Ras inhibitors were shown to induce autophagy in several cancer cell lines. PMID:24583697

  8. Regulating the Regulator: Post-Translational Modification of Ras

    PubMed Central

    Ahearn, Ian M.; Haigis, Kevin; Bar-Sagi, Dafna; Philips, Mark R.

    2013-01-01

    Ras proteins are monomeric GTPases that act as binary molecular switches to regulate a wide range of cellular processes. The exchange of GTP for GDP on Ras is regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), which regulate the activation state of Ras without covalently modifying it. In contrast, post-translational modifications (PTMs) of Ras proteins direct them to various cellular membranes and, in some cases, modulate GTP–GDP exchange. Important Ras PTMs include the constitutive and irreversible remodelling of its C-terminal CAAX motif by farnesylation, proteolysis and methylation, reversible palmitoylation, and conditional modifications including phosphorylation, peptidyl-proly isomerisation, mono- and di-ubiquitination, nitrosylation, ADP ribosylation and glucosylation. PMID:22189424

  9. Tornado missile simulation and design methodology. Volume 1: simulation methodology, design applications, and TORMIS computer code. Final report

    SciTech Connect

    Twisdale, L.A.; Dunn, W.L.

    1981-08-01

    A probabilistic methodology has been developed to predict the probabilities of tornado-propelled missiles impacting and damaging nuclear power plant structures. Mathematical models of each event in the tornado missile hazard have been developed and sequenced to form an integrated, time-history simulation methodology. The models are data based where feasible. The data include documented records of tornado occurrence, field observations of missile transport, results of wind tunnel experiments, and missile impact tests. Probabilistic Monte Carlo techniques are used to estimate the risk probabilities. The methodology has been encoded in the TORMIS computer code to facilitate numerical analysis and plant-specific tornado missile probability assessments. Sensitivity analyses have been performed on both the individual models and the integrated methodology, and risk has been assessed for a hypothetical nuclear power plant design case study.

  10. Tyrosine phosphorylation of RAS by ABL allosterically enhances effector binding

    PubMed Central

    Ting, Pamela Y.; Johnson, Christian W.; Fang, Cong; Cao, Xiaoqing; Graeber, Thomas G.; Mattos, Carla; Colicelli, John

    2015-01-01

    RAS proteins are signal transduction gatekeepers that mediate cell growth, survival, and differentiation through interactions with multiple effector proteins. The RAS effector RAS- and RAB-interacting protein 1 (RIN1) activates its own downstream effectors, the small GTPase RAB5 and the tyrosine kinase Abelson tyrosine-protein kinase (ABL), to modulate endocytosis and cytoskeleton remodeling. To identify ABL substrates downstream of RAS-to-RIN1 signaling, we examined human HEK293T cells overexpressing components of this pathway. Proteomic analysis revealed several novel phosphotyrosine peptides, including Harvey rat sarcoma oncogene (HRAS)-pTyr137. Here we report that ABL phosphorylates tyrosine 137 of H-, K-, and NRAS. Increased RIN1 levels enhanced HRAS-Tyr137 phosphorylation by nearly 5-fold, suggesting that RAS-stimulated RIN1 can drive ABL-mediated RAS modification in a feedback circuit. Tyr137 is well conserved among RAS orthologs and is part of a transprotein H-bond network. Crystal structures of HRASY137F and HRASY137E revealed conformation changes radiating from the mutated residue. Although consistent with Tyr137 participation in allosteric control of HRAS function, the mutations did not alter intrinsic GTP hydrolysis rates in vitro. HRAS-Tyr137 phosphorylation enhanced HRAS signaling capacity in cells, however, as reflected by a 4-fold increase in the association of phosphorylated HRASG12V with its effector protein RAF proto-oncogene serine/threonine protein kinase 1 (RAF1). These data suggest that RAS phosphorylation at Tyr137 allosterically alters protein conformation and effector binding, providing a mechanism for effector-initiated modulation of RAS signaling.—Ting, P. Y., Johnson, C. W., Fang, C., Cao, X., Graeber, T. G., Mattos, C., Colicelli, J. Tyrosine phosphorylation of RAS by ABL allosterically enhances effector binding. PMID:25999467

  11. Regulation of collagen I gene expression by ras.

    PubMed Central

    Slack, J L; Parker, M I; Robinson, V R; Bornstein, P

    1992-01-01

    Although transformation of rodent fibroblasts can lead to dramatic changes in expression of extracellular matrix genes, the molecular basis and physiological significance of these changes remain poorly understood. In this study, we have investigated the mechanism(s) by which ras affects expression of the genes encoding type I collagen. Levels of both alpha 1(I) and alpha 2(I) collagen mRNAs were markedly reduced in Rat 1 fibroblasts overexpressing either the N-rasLys-61 or the Ha-rasVal-12 oncogene. In fibroblasts conditionally transformed with N-rasLys-61, alpha 1(I) transcript levels began to decline within 8 h of ras induction and reached 1 to 5% of control levels after 96 h. In contrast, overexpression of normal ras p21 had no effect on alpha 1(I) or alpha 2(I) mRNA levels. Nuclear run-on experiments demonstrated that the transcription rates of both the alpha 1(I) and alpha 2(I) genes were significantly reduced in ras-transformed cells compared with those in parental cells. In addition, the alpha 1(I) transcript was less stable in transformed cells. Chimeric plasmids containing up to 3.6 kb of alpha 1(I) 5'-flanking DNA and up to 2.3 kb of the 3'-flanking region were expressed at equivalent levels in both normal and ras-transformed fibroblasts. However, a cosmid clone containing the entire mouse alpha 1(I) gene, including 3.7 kb of 5'- and 4 kb of 3'-flanking DNA, was expressed at reduced levels in fibroblasts overexpressing oncogenic ras. We conclude that oncogenic ras regulates the type I collagen genes at both transcriptional and posttranscriptional levels and that this effect, at least for the alpha 1(I) gene, may be mediated by sequences located either within the body of the gene itself or in the distal 3'-flanking region. Images PMID:1406656

  12. Mutations in ras genes in experimental tumours of rodents.

    PubMed

    Sills, R C; Boorman, G A; Neal, J E; Hong, H L; Devereux, T R

    1999-01-01

    Studies of carcinogenesis in rodents are valuable for examining mutagenesis in vivo. An advantage of evaluating the frequency and spectra of ras mutations in chemically induced neoplasms is that the additional data at the molecular level indicate whether the carcinogenic effect is due to the chemical and is not a spontaneous event, as illustrated by the numerous examples in Appendices 1 and 2. In addition, data on the frequency and spectra of ras mutations in spontaneous and chemically induced neoplasms clearly expand the toxicological database by providing information helpful for understanding the pathogenesis of carcinogenesis. For example: (1) ozone-induced lung neoplasms had two unique mutations, one (codon 61 K-ras CTA mutation) consistent with a direct genotoxic event and a second (codon 12 K-ras G --> T transversion) consistent with an indirect genotoxic effect; (2) isoprene-induced Harderian gland neoplasms had a unique K-ras A --> T transversion at codon 61 which provided evidence that formation of an epoxide intermediate was involved; (3) 1,3-butadiene-induced neoplasms had a characteristic K-ras G --> C transversion mutation at codon 13 which was also consistent with a chemical-specific effect; (4) methylene chloride-induced liver neoplasms had an H-ras mutation profile at codon 61 similar to that of spontaneous tumours, suggesting that methylene chloride promotes cells with 'spontaneously initiated' ras mutations and (5) oxazepam-induced liver neoplasms had a low frequency of ras mutations, suggesting a nonmutagenic pathway of carcinogenesis. By extending the evaluation of rodent tumours to include molecular studies on ras mutation spectra and abnormalities in other cancer genes with human homologues, a number of hypotheses can be tested, allowing the most complete understanding of carcinogenesis in rodents and in potential extrapolation to the human risk situation. PMID:10353384

  13. Comparison of the Effects of RAS vs. Kain-Fritsch Convective Schemes on Katrina Forecasts with GEOS-5

    NASA Technical Reports Server (NTRS)

    Miller, Timothy L.; Cohen, Charles; Paxton, Jessica; Robertson, F. R. (Pete)

    2009-01-01

    Global forecasts were made with the 0.25-degree latitude version of GEOS-5, with the RAS scheme and with the Kain-Fritsch scheme. Examination was made of the Katrina (2005) hurricane simulation. Replacement of the RAS convective scheme with the K-F scheme results in a much more vigorous Katrina, closer to reality. Still, the result is not as vigorous as reality. In terms of wind maximum, the gap was closed by 50%. The result seems to be due to the RAS scheme drying out the boundary layer, thus hampering the grid-scale secondary circulation and attending cyclone development. The RAS case never developed a full warm core, whereas the K-F case did. Not shown here: The K-F scheme also resulted in a more vigorous storm than when GEOS-5 is run with no convective parameterization. Also not shown: An experiment in which the RAS firing level was moved up by 3 model levels resulted in a stronger, warm-core storm, though not as strong as the K-F case. Effects on storm track were noticed, but not studied.

  14. 1, 25 Dihydroxyvitamin D Regulation of Glucose Metabolism in Harvey-ras Transformed MCF10A Human Breast Epithelial Cells

    PubMed Central

    Zheng, Wei; Tayyari, Fariba; Gowda, G. A. Nagana; Raftery, Daniel; McLamore, Eric S.; Shi, Jin; Porterfield, D. Marshall; Donkin, Shawn; Bequette, Brian; Teegarden, Dorothy

    2014-01-01

    This study was designed to investigate the impact of 1,25 dihydroxyvitamin D (1,25(OH)2D) on glucose metabolism during early cancer progression. Untransformed and ras-oncogene transfected (ras) MCF10A human breast epithelial cells were employed to model early breast cancer progression. 1,25(OH)2D modified the response of the ras cells to glucose restriction, suggesting 1,25(OH)2D may reduce the ras cell glucose addiction noted in cancer cells. To understand the 1,25(OH)2D regulation of glucose metabolism, following four-day 1,25(OH)2D treatment, metabolite fluxes at the cell membrane were measured by a nanoprobe biosensor, [13C6]glucose flux by 13C-mass isotopomer distribution analysis of media metabolites, intracellular metabolite levels by NMR, and gene expression of related enzymes assessed. Treatment with 1,25(OH)2D reduced glycolysis as flux of glucose to 3-phosphoglycerate was reduced by 15% (P = 0.017) and 32% (P < 0.003) in MCF10A and ras cells respectively. In the ras cells, 1,25(OH)2D reduced lactate dehydrogenase activity by 15% (P < 0.05) with a concomitant 10% reduction in the flux of glucose to lactate (P = 0.006), and reduction in the level of intracellular lactate by 55% (P = 0.029). Treatment with 1,25(OH)2D reduced flux of glucose to acetyl-coA 24% (P = 0.002) and 41% (P < 0.001), and flux to oxaloacetate 34% (P = 0.003) and 33% (P = 0.027) in the MCF10A and ras cells, respectively, suggesting a reduction in tricarboxylic acid (TCA) cycle activity. The results suggest a novel mechanism involving the regulation of glucose metabolism by which 1,25(OH)2D may prevent breast cancer progression. PMID:23619337

  15. Regional scale flood modeling using NEXRAD rainfall, GIS, and HEC-HMS/RAS: a case study for the San Antonio River Basin Summer 2002 storm event.

    PubMed

    Knebl, M R; Yang, Z-L; Hutchison, K; Maidment, D R

    2005-06-01

    This paper develops a framework for regional scale flood modeling that integrates NEXRAD Level III rainfall, GIS, and a hydrological model (HEC-HMS/RAS). The San Antonio River Basin (about 4000 square miles, 10,000 km2) in Central Texas, USA, is the domain of the study because it is a region subject to frequent occurrences of severe flash flooding. A major flood in the summer of 2002 is chosen as a case to examine the modeling framework. The model consists of a rainfall-runoff model (HEC-HMS) that converts precipitation excess to overland flow and channel runoff, as well as a hydraulic model (HEC-RAS) that models unsteady state flow through the river channel network based on the HEC-HMS-derived hydrographs. HEC-HMS is run on a 4 x 4 km grid in the domain, a resolution consistent with the resolution of NEXRAD rainfall taken from the local river authority. Watershed parameters are calibrated manually to produce a good simulation of discharge at 12 subbasins. With the calibrated discharge, HEC-RAS is capable of producing floodplain polygons that are comparable to the satellite imagery. The modeling framework presented in this study incorporates a portion of the recently developed GIS tool named Map to Map that has been created on a local scale and extends it to a regional scale. The results of this research will benefit future modeling efforts by providing a tool for hydrological forecasts of flooding on a regional scale. While designed for the San Antonio River Basin, this regional scale model may be used as a prototype for model applications in other areas of the country. PMID:15854726

  16. Positional glow curve simulation for thermoluminescent detector (TLD) system design

    NASA Astrophysics Data System (ADS)

    Branch, C. J.; Kearfott, K. J.

    1999-02-01

    Multi- and thin element dosimeters, variable heating rate schemes, and glow-curve analysis have been employed to improve environmental and personnel dosimetry using thermoluminescent detectors (TLDs). Detailed analysis of the effects of errors and optimization of techniques would be highly desirable. However, an understanding of the relationship between TL light production, light attenuation, and precise heating schemes is made difficult because of experimental challenges involved in measuring positional TL light production and temperature variations as a function of time. This work reports the development of a general-purpose computer code, thermoluminescent detector simulator, TLD-SIM, to simulate the heating of any TLD type using a variety of conventional and experimental heating methods including pulsed focused or unfocused lasers with Gaussian or uniform cross sections, planchet, hot gas, hot finger, optical, infrared, or electrical heating. TLD-SIM has been used to study the impact on the TL light production of varying the input parameters which include: detector composition, heat capacity, heat conductivity, physical size, and density; trapped electron density, the frequency factor of oscillation of electrons in the traps, and trap-conduction band potential energy difference; heating scheme source terms and heat transfer boundary conditions; and TL light scatter and attenuation coefficients. Temperature profiles and glow curves as a function of position time, as well as the corresponding temporally and/or spatially integrated glow values, may be plotted while varying any of the input parameters. Examples illustrating TLD system functions, including glow curve variability, will be presented. The flexible capabilities of TLD-SIM promises to enable improved TLD system design.

  17. Design and simulation of a hybrid dielectric waveguide

    NASA Astrophysics Data System (ADS)

    Aryal, Krishna Prasad

    Waveguides, in general are used as a means to route photons. Traditional dielectric waveguides, composed of a high index core surrounded by a low index cladding, produce maximum field intensities far from dielectric interfaces. This thesis presents the design of a plasmonic enhanced waveguide, which relocates the maximum optical field intensity from the center of the waveguide to an interfacial region defined by a dielectric and a negative index material. This is accomplished through the use of a metal film, positioned on top of a traditional ridge waveguide in those places where one wishes to excite a plasmon mode as opposed to the more traditional dielectric mode. Plasmon modes have their highest field intensity at the interface located between the metal and the dielectric. In this thesis, the waveguide dimensions of a hybrid dielectric waveguide are determined with the intent of producing single mode operation for a ridge waveguide with and without metal on top. A commercial Eigen mode solver (MODE Lumerical) is used to obtain all field profiles, waveguide effective index and waveguide loss. Multiple simulations were used to design a waveguide, which supports a single plasmonic mode when the metal film is in place and a single dielectric mode when the metal film is absent. Such a waveguide is expected to find use in the field of integrated quantum optics where quantum dots, defined by near surface confining potentials, require high interfacial fields for maximum dot/field interactions. Further, based on the final waveguide design height of ( 5microm ) and width of ( 7.9microm ), an effective index of ( 3.687 ) results when operated in the plasmon mode and (3.619) when operated in dielectric mode. This change in refractive index suggests such hybrid dielectric/plasmon waveguides can be used for the design of Bragg reflectors leading to plasmonic cavities, which, when coupled to the proposed near surface located quantum dots, can be used for the production and

  18. Design tradeoffs in the development of the advanced multispectral simulation test acceptance resource (AMSTAR) HWIL facilities

    NASA Astrophysics Data System (ADS)

    LeSueur, Kenneth G.; Almendinger, Frank J.

    2007-04-01

    The Army's Advanced Multispectral Simulation Test Acceptance Resource (AMSTAR) is a suite of missile Hardware-In-the-Loop (HWIL) simulation / test capabilities designed to support testing from concept through production. This paper presents the design tradeoffs that were conducted in the development of the AMSTAR sensor stimulators and the flight motion simulators. The AMSTAR facility design includes systems to stimulate each of the Millimeter Wave (MMW), Infrared (IR), and Semi-Active Laser (SAL) sensors. The flight motion simulator (FMS) performance was key to the success of the simulation but required many concessions to accommodate the design considerations for the tri-mode stimulation systems.

  19. Evolution of ephemerides EPM of IAA RAS

    NASA Astrophysics Data System (ADS)

    Pitjeva, E.

    2015-08-01

    The evolution of numerical EPM ephemerides of the IAA RAS from available EPM2004, EPM2008, EPM2011, to the new EPM2014 version is presented briefly. The comparison progress of ephemerides includes: the growing database of different types of observations from classical optical to radio technical of spacecraft from 1913 to 2014, enlarged up to more 800000 measurements; improved dynamical model from mutual perturbations of all planets, the Sun, the Moon, 301 largest asteroids to additional perturbations from of 30 largest trans-neptunian objects (TNO) and perturbations from remaining smaller asteroids and TNO modeled by the two-dimensional asteroid ring and the one-dimensional TNO ring; program software ERA-7 to ERA-8.

  20. Design and simulation of an intelligent mass-storage architecture

    SciTech Connect

    Penaloza, M.A.

    1989-01-01

    This dissertation presents the design of an Intelligent Mass Storage Architecture (IMSA) that not only increases the disk 1/0 bandwidth but also provides database transparency and data consistency. The database transparency characteristic relieves a host system from the overhead incurred in accessing and maintaining the physical database on disk devices. The data consistency characteristic refers to the capability of IMSA in evaluating a set of integrity constraints (IC's) that represent semantic rules required to preserve the consistency of the database. This evaluation is performed by specialized filter processors. This dissertation presents: (a) a precise definition of any filter operation by means of a canonical filter form, (b) the analysis of the different types of IC's that might be defined in a database, (c) the inclusion of IC's and the selection and projection operations within the filter concept, (d) the integration of these IC's and query filters, (e) the simplification of IC's into'cheaper' IC's by using several simplification techniques, and (f) the evaluation of these filters by hardware. IMSA is composed of several units which are structured as a hierarchical organization. Parallelism, concurrency, dataflow execution, disk cache memory, and multiport memories are the main concepts and techniques used and/or inspired by the design of IMSA. These techniques and the hierarchical structure contribute to its efficiency. IMSA's performance was analyzed using simulation and analytical models. It was compared with four different host system configurations. The results from these two models showed a considerable advantage of IMSA over any of the host configurations with respect to the evaluation of IC's and query filters.

  1. Design studies for the transmission simulator method of experimental dynamic substructuring.

    SciTech Connect

    Mayes, Randall Lee; Arviso, Michael

    2010-05-01

    In recent years, a successful method for generating experimental dynamic substructures has been developed using an instrumented fixture, the transmission simulator. The transmission simulator method solves many of the problems associated with experimental substructuring. These solutions effectively address: (1) rotation and moment estimation at connection points; (2) providing substructure Ritz vectors that adequately span the connection motion space; and (3) adequately addressing multiple and continuous attachment locations. However, the transmission simulator method may fail if the transmission simulator is poorly designed. Four areas of the design addressed here are: (1) designating response sensor locations; (2) designating force input locations; (3) physical design of the transmission simulator; and (4) modal test design. In addition to the transmission simulator design investigations, a review of the theory with an example problem is presented.

  2. Heat-load simulator for heat sink design

    NASA Technical Reports Server (NTRS)

    Dunleavy, A. M.; Vaughn, T. J.

    1968-01-01

    Heat-load simulator is fabricated from 1/4-inch aluminum plate with a contact surface equal in dimensions and configuration to those of the electronic installation. The method controls thermal output to simulate actual electronic component thermal output.

  3. Quadruple wild-type (WT) GIST: defining the subset of GIST that lacks abnormalities of KIT, PDGFRA, SDH, or RAS signaling pathways

    PubMed Central

    Pantaleo, Maria A; Nannini, Margherita; Corless, Christopher L; Heinrich, Michael C

    2015-01-01

    A subset of GISTs lack mutations in the KIT/PDGFRA or RAS pathways and yet retain an intact succinate dehydrogensase (SDH) complex. We propose that these KIT/PDGFRA/SDH/RAS-P WT GIST tumors be designated as quadruple wild-type (WT) GIST. Further molecular and clinicophatological characterization of quadruple WT GIST will help to determine their prognosis as well as assist in the optimization of medical management, including clinical test of novel therapies. PMID:25165019

  4. Quadruple wild-type (WT) GIST: defining the subset of GIST that lacks abnormalities of KIT, PDGFRA, SDH, or RAS signaling pathways.

    PubMed

    Pantaleo, Maria A; Nannini, Margherita; Corless, Christopher L; Heinrich, Michael C

    2015-01-01

    A subset of GISTs lack mutations in the KIT/PDGFRA or RAS pathways and yet retain an intact succinate dehydrogensase (SDH) complex. We propose that these KIT/PDGFRA/SDH/RAS-P WT GIST tumors be designated as quadruple wild-type (WT) GIST. Further molecular and clinicophatological characterization of quadruple WT GIST will help to determine their prognosis as well as assist in the optimization of medical management, including clinical test of novel therapies. PMID:25165019

  5. Interactive Graphics Simulator: Design, Development, and Effectiveness/Cost Evaluation. Final Report.

    ERIC Educational Resources Information Center

    Pieper, William J.; And Others

    This study was initiated to design, develop, implement, and evaluate a videodisc-based simulator system, the Interactive Graphics Simulator (IGS) for 6883 Converter Flight Control Test Station training at Lowry Air Force Base, Colorado. The simulator provided a means for performing task analysis online, developing simulations from the task…

  6. Effects of Thinking Style on Design Strategies: Using Bridge Construction Simulation Programs

    ERIC Educational Resources Information Center

    Sun, Chuen-Tsai; Wang, Dai-Yi; Chang, Yu-Yeh

    2013-01-01

    Computer simulation users can freely control operational factors and simulation results, repeat processes, make changes, and learn from simulation environment feedback. The focus of this paper is on simulation-based design tools and their effects on student learning processes in a group of 101 Taiwanese senior high school students. Participants…

  7. Simulation-based optimal Bayesian experimental design for nonlinear systems

    SciTech Connect

    Huan, Xun; Marzouk, Youssef M.

    2013-01-01

    The optimal selection of experimental conditions is essential to maximizing the value of data for inference and prediction, particularly in situations where experiments are time-consuming and expensive to conduct. We propose a general mathematical framework and an algorithmic approach for optimal experimental design with nonlinear simulation-based models; in particular, we focus on finding sets of experiments that provide the most information about targeted sets of parameters. Our framework employs a Bayesian statistical setting, which provides a foundation for inference from noisy, indirect, and incomplete data, and a natural mechanism for incorporating heterogeneous sources of information. An objective function is constructed from information theoretic measures, reflecting expected information gain from proposed combinations of experiments. Polynomial chaos approximations and a two-stage Monte Carlo sampling method are used to evaluate the expected information gain. Stochastic approximation algorithms are then used to make optimization feasible in computationally intensive and high-dimensional settings. These algorithms are demonstrated on model problems and on nonlinear parameter inference problems arising in detailed combustion kinetics.

  8. Algorithm design for a gun simulator based on image processing

    NASA Astrophysics Data System (ADS)

    Liu, Yu; Wei, Ping; Ke, Jun

    2015-08-01

    In this paper, an algorithm is designed for shooting games under strong background light. Six LEDs are uniformly distributed on the edge of a game machine screen. They are located at the four corners and in the middle of the top and the bottom edges. Three LEDs are enlightened in the odd frames, and the other three are enlightened in the even frames. A simulator is furnished with one camera, which is used to obtain the image of the LEDs by applying inter-frame difference between the even and odd frames. In the resulting images, six LED are six bright spots. To obtain the LEDs' coordinates rapidly, we proposed a method based on the area of the bright spots. After calibrating the camera based on a pinhole model, four equations can be found using the relationship between the image coordinate system and the world coordinate system with perspective transformation. The center point of the image of LEDs is supposed to be at the virtual shooting point. The perspective transformation matrix is applied to the coordinate of the center point. Then we can obtain the virtual shooting point's coordinate in the world coordinate system. When a game player shoots a target about two meters away, using the method discussed in this paper, the calculated coordinate error is less than ten mm. We can obtain 65 coordinate results per second, which meets the requirement of a real-time system. It proves the algorithm is reliable and effective.

  9. Design and Simulation of Optically Actuated Bistable MEMS

    NASA Astrophysics Data System (ADS)

    Lucas, Thomas; Moiseeva, Evgeniya; Harnett, Cindy

    2012-02-01

    In this project, bistable three-dimensional MEMS actuators are designed to be optically switched between stable states for biological research applications. The structure is a strained rectangular frame created with stress-mismatched metal-oxide bilayers. The devices curl into an arc in one of two directions tangent to the substrate, and can switch orientation when regions are selectively heated. The heating is powered by infrared laser, and localized with patterned infrared-resonant gold nanoparticles on critical regions. The enhanced energy absorption on selected areas provides switching control and heightened response to narrow-band infrared light. Coventorware has been used for finite element analysis of the system. The numerical simulations indicate that it has two local minimum states with extremely rapid transition time (<<0.1 s) when the structure is thermally deformed. Actuation at laser power and thermal limits compatible with physiological applications will enable microfluidic pumping elements and fundamental studies of tissue response to three-dimensional mechanical stimuli, artificial-muscle based pumps and other biomedical devices triggered by tissue-permeant infrared light.

  10. RasGRP3 regulates the migration of glioma cells via interaction with Arp3

    PubMed Central

    Lee, Hae Kyung; Finniss, Susan; Cazacu, Simona; Xiang, Cunli; Poisson, Laila M.; Blumberg, Peter M.; Brodie, Chaya

    2015-01-01

    Glioblastoma (GBM), the most aggressive primary brain tumors, are highly infiltrative. Although GBM express high Ras activity and Ras proteins have been implicated in gliomagenesis, Ras-activating mutations are not frequent in these tumors. RasGRP3, an important signaling protein responsive to diacylglycerol (DAG), increases Ras activation. Here, we examined the expression and functions of RasGRP3 in GBM and glioma cells. RasGRP3 expression was upregulated in GBM specimens and glioma stem cells compared with normal brains and neural stem cells, respectively. RasGRP3 activated Ras and Rap1 in glioma cells and increased cell migration and invasion partially via Ras activation. Using pull-down assay and mass spectroscopy we identified the actin-related protein, Arp3, as a novel interacting protein of RasGRP3. The interaction of RasGRP3 and Arp3 was validated by immunofluorescence staining and co-immunoprecipitation, and PMA, which activates RasGRP3 and induces its translocation to the peri-nuclear region, increased the association of Arp3 and RasGRP3. Arp3 was upregulated in GBM, regulated cell spreading and migration and its silencing partially decreased these effects of RasGRP3 in glioma cells. In summary, RasGRP3 acts as an important integrating signaling protein of the DAG and Ras signaling pathways and actin polymerization and represents an important therapeutic target in GBM. PMID:25682201

  11. Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis

    PubMed Central

    Bunda, Severa; Burrell, Kelly; Heir, Pardeep; Zeng, Lifan; Alamsahebpour, Amir; Kano, Yoshihito; Raught, Brian; Zhang, Zhong-Yin; Zadeh, Gelareh; Ohh, Michael

    2015-01-01

    Ras is phosphorylated on a conserved tyrosine at position 32 within the switch I region via Src kinase. This phosphorylation inhibits the binding of effector Raf while promoting the engagement of GTPase-activating protein (GAP) and GTP hydrolysis. Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. In comparison to normal astrocytes, SHP2 activity is elevated in astrocytes isolated from glioblastoma multiforme (GBM)-prone H-Ras(12V) knock-in mice as well as in glioma cell lines and patient-derived GBM specimens exhibiting hyperactive Ras. Pharmacologic inhibition of SHP2 activity attenuates cell proliferation, soft-agar colony formation and orthotopic GBM growth in NOD/SCID mice and decelerates the progression of low-grade astrocytoma to GBM in a spontaneous transgenic glioma mouse model. These results identify SHP2 as a direct activator of Ras and a potential therapeutic target for cancers driven by a previously ‘undruggable' oncogenic or hyperactive Ras. PMID:26617336

  12. Analysis of Ras-induced overproliferation in Drosophila hemocytes.

    PubMed Central

    Asha, H; Nagy, Istvan; Kovacs, Gabor; Stetson, Daniel; Ando, Istvan; Dearolf, Charles R

    2003-01-01

    We use the Drosophila melanogaster larval hematopoietic system as an in vivo model for the genetic and functional genomic analysis of oncogenic cell overproliferation. Ras regulates cell proliferation and differentiation in multicellular eukaryotes. To further elucidate the role of activated Ras in cell overproliferation, we generated a collagen promoter-Gal4 strain to overexpress Ras(V12) in Drosophila hemocytes. Activated Ras causes a dramatic increase in the number of circulating larval hemocytes (blood cells), which is caused by cellular overproliferation. This phenotype is mediated by the Raf/MAPK pathway. The mutant hemocytes retain the ability to phagocytose bacteria as well as to differentiate into lamellocytes. Microarray analysis of hemocytes overexpressing Ras(V12) vs. Ras(+) identified 279 transcripts that are differentially expressed threefold or more in hemocytes expressing activated Ras. This work demonstrates that it will be feasible to combine genetic and functional genomic approaches in the Drosophila hematopoietic system to systematically identify oncogene-specific downstream targets. PMID:12586708

  13. Oncogenic Ras stimulates Eiger/TNF exocytosis to promote growth

    PubMed Central

    Chabu, Chiswili; Xu, Tian

    2014-01-01

    Oncogenic mutations in Ras deregulate cell death and proliferation to cause cancer in a significant number of patients. Although normal Ras signaling during development has been well elucidated in multiple organisms, it is less clear how oncogenic Ras exerts its effects. Furthermore, cancers with oncogenic Ras mutations are aggressive and generally resistant to targeted therapies or chemotherapy. We identified the exocytosis component Sec15 as a synthetic suppressor of oncogenic Ras in an in vivo Drosophila mosaic screen. We found that oncogenic Ras elevates exocytosis and promotes the export of the pro-apoptotic ligand Eiger (Drosophila TNF). This blocks tumor cell death and stimulates overgrowth by activating the JNK-JAK-STAT non-autonomous proliferation signal from the neighboring wild-type cells. Inhibition of Eiger/TNF exocytosis or interfering with the JNK-JAK-STAT non-autonomous proliferation signaling at various steps suppresses oncogenic Ras-mediated overgrowth. Our findings highlight important cell-intrinsic and cell-extrinsic roles of exocytosis during oncogenic growth and provide a new class of synthetic suppressors for targeted therapy approaches. PMID:25411211

  14. Purpose and Learning Benefits of Simulations: A Design and Development Perspective.

    ERIC Educational Resources Information Center

    Goosen, Kenneth R.; Jensen, Ron; Wells, Robert

    2001-01-01

    Considers the role of the simulation designer in the development of business enterprise simulations used in collegiate business education. Topics include the designer's knowledge domain; conflicting business administration theories in accounting, finance, economics, marketing, production, and income tax; and other designer issues. (LRW)

  15. Gas-grain simulation experiment module conceptual design and gas-grain simulation facility breadboard development

    NASA Technical Reports Server (NTRS)

    Zamel, James M.; Petach, Michael; Gat, Nahum; Kropp, Jack; Luong, Christina; Wolff, Michael

    1993-01-01

    This report delineates the Option portion of the Phase A Gas-Grain Simulation Facility study. The conceptual design of a Gas-Grain Simulation Experiment Module (GGSEM) for Space Shuttle Middeck is discussed. In addition, a laboratory breadboard was developed during this study to develop a key function for the GGSEM and the GGSF, specifically, a solid particle cloud generating device. The breadboard design and test results are discussed and recommendations for further studies are included. The GGSEM is intended to fly on board a low earth orbit (LEO), manned platform. It will be used to perform a subset of the experiments planned for the GGSF for Space Station Freedom, as it can partially accommodate a number of the science experiments. The outcome of the experiments performed will provide an increased understanding of the operational requirements for the GGSF. The GGSEM will also act as a platform to accomplish technology development and proof-of-principle experiments for GGSF hardware, and to verify concepts and designs of hardware for GGSF. The GGSEM will allow assembled subsystems to be tested to verify facility level operation. The technology development that can be accommodated by the GGSEM includes: GGSF sample generation techniques, GGSF on-line diagnostics techniques, sample collection techniques, performance of various types of sensors for environmental monitoring, and some off-line diagnostics. Advantages and disadvantages of several LEO platforms available for GGSEM applications are identified and discussed. Several of the anticipated GGSF experiments require the deagglomeration and dispensing of dry solid particles into an experiment chamber. During the GGSF Phase A study, various techniques and devices available for the solid particle aerosol generator were reviewed. As a result of this review, solid particle deagglomeration and dispensing were identified as key undeveloped technologies in the GGSF design. A laboratory breadboard version of a solid

  16. RAS Synthetic Lethal Screens Revisited: Still Seeking the Elusive Prize?

    PubMed Central

    Downward, Julian

    2015-01-01

    The RAS genes are critical oncogenic drivers activated by point mutation in some 20% of human malignancies. However, no pharmacological approaches to targeting RAS proteins directly have yet succeeded, leading to suggestions that these proteins may be “undruggable.” This has led to two alternative indirect approaches to targeting RAS function in cancer. One has been to target RAS signaling pathways downstream at tractable enzymes such as kinases, particularly in combination. The other, which is the focus of this review, has been to seek targets that are essential in cells bearing an activated RAS oncogene, but not those without. This synthetic lethal approach, while rooted in ideas from invertebrate genetics, has been inspired most strongly by the successful use of PARP inhibitors, such as olaparib, in the clinic to treat BRCA defective cancers. Several large-scale screens have been carried out using RNA interference-mediated expression silencing to find genes that are uniquely essential to RAS mutant but not wild type cells. These screens have been notable for the low degree of overlap between their results, with the possible exception of proteasome components, and have yet to lead to successful new clinical approaches to the treatment of RAS mutant cancers. Possible reasons for these disappointing results are discussed here, along with a re-evaluation of the approaches taken. Based on experience to date, RAS synthetic lethality has so far fallen some way short of its original promise and remains unproven as an approach to finding effective new ways of tackling RAS mutant cancers. PMID:25878361

  17. Serum-dependent transcriptional networks identify distinct functional roles for H-Ras and N-Ras during initial stages of the cell cycle

    PubMed Central

    2009-01-01

    Background Using oligonucleotide microarrays, we compared transcriptional profiles corresponding to the initial cell cycle stages of mouse fibroblasts lacking the small GTPases H-Ras and/or N-Ras with those of matching, wild-type controls. Results Serum-starved wild-type and knockout ras fibroblasts had very similar transcriptional profiles, indicating that H-Ras and N-Ras do not significantly control transcriptional responses to serum deprivation stress. In contrast, genomic disruption of H-ras or N-ras, individually or in combination, determined specific differential gene expression profiles in response to post-starvation stimulation with serum for 1 hour (G0/G1 transition) or 8 hours (mid-G1 progression). The absence of N-Ras caused significantly higher changes than the absence of H-Ras in the wave of transcriptional activation linked to G0/G1 transition. In contrast, the absence of H-Ras affected the profile of the transcriptional wave detected during G1 progression more strongly than did the absence of N-Ras. H-Ras was predominantly functionally associated with growth and proliferation, whereas N-Ras had a closer link to the regulation of development, the cell cycle, immunomodulation and apoptosis. Mechanistic analysis indicated that extracellular signal-regulated kinase (ERK)-dependent activation of signal transducer and activator of transcription 1 (Stat1) mediates the regulatory effect of N-Ras on defense and immunity, whereas the pro-apoptotic effects of N-Ras are mediated through ERK and p38 mitogen-activated protein kinase signaling. Conclusions Our observations confirm the notion of an absolute requirement for different peaks of Ras activity during the initial stages of the cell cycle and document the functional specificity of H-Ras and N-Ras during those processes. PMID:19895680

  18. PGA1-induced apoptosis involves specific activation of H-Ras and N-Ras in cellular endomembranes.

    PubMed

    Anta, B; Pérez-Rodríguez, A; Castro, J; García-Domínguez, C A; Ibiza, S; Martínez, N; Durá, L M; Hernández, S; Gragera, T; Peña-Jiménez, D; Yunta, M; Zarich, N; Crespo, P; Serrador, J M; Santos, E; Muñoz, A; Oliva, J L; Rojas-Cabañeros, J M

    2016-01-01

    The cyclopentenone prostaglandin A1 (PGA1) is an inducer of cell death in cancer cells. However, the mechanism that initiates this cytotoxic response remains elusive. Here we report that PGA1 triggers apoptosis by a process that entails the specific activation of H- and N-Ras isoforms, leading to caspase activation. Cells without H- and N-Ras did not undergo apoptosis upon PGA1 treatment; in these cells, the cellular demise was rescued by overexpression of either H-Ras or N-Ras. Consistently, the mutant H-Ras-C118S, defective for binding PGA1, did not produce cell death. Molecular analysis revealed a key role for the RAF-MEK-ERK signaling pathway in the apoptotic process through the induction of calpain activity and caspase-12 cleavage. We propose that PGA1 evokes a specific physiological cell death program, through H- and N-Ras, but not K-Ras, activation at endomembranes. Our results highlight a novel mechanism that may be of potential interest for tumor treatment. PMID:27468687

  19. PGA1-induced apoptosis involves specific activation of H-Ras and N-Ras in cellular endomembranes

    PubMed Central

    Anta, B; Pérez-Rodríguez, A; Castro, J; García- Domínguez, C A; Ibiza, S; Martínez, N; Durá, L M; Hernández, S; Gragera, T; Peña-Jiménez, D; Yunta, M; Zarich, N; Crespo, P; Serrador, J M; Santos, E; Muñoz, A; Oliva, J L; Rojas-Cabañeros, J M

    2016-01-01

    The cyclopentenone prostaglandin A1 (PGA1) is an inducer of cell death in cancer cells. However, the mechanism that initiates this cytotoxic response remains elusive. Here we report that PGA1 triggers apoptosis by a process that entails the specific activation of H- and N-Ras isoforms, leading to caspase activation. Cells without H- and N-Ras did not undergo apoptosis upon PGA1 treatment; in these cells, the cellular demise was rescued by overexpression of either H-Ras or N-Ras. Consistently, the mutant H-Ras-C118S, defective for binding PGA1, did not produce cell death. Molecular analysis revealed a key role for the RAF-MEK-ERK signaling pathway in the apoptotic process through the induction of calpain activity and caspase-12 cleavage. We propose that PGA1 evokes a specific physiological cell death program, through H- and N-Ras, but not K-Ras, activation at endomembranes. Our results highlight a novel mechanism that may be of potential interest for tumor treatment. PMID:27468687

  20. Designing Better Scaffolding in Teaching Complex Systems with Graphical Simulations

    NASA Astrophysics Data System (ADS)

    Li, Na

    Complex systems are an important topic in science education today, but they are usually difficult for secondary-level students to learn. Although graphic simulations have many advantages in teaching complex systems, scaffolding is a critical factor for effective learning. This dissertation study was conducted around two complementary research questions on scaffolding: (1) How can we chunk and sequence learning activities in teaching complex systems? (2) How can we help students make connections among system levels across learning activities (level bridging)? With a sample of 123 seventh-graders, this study employed a 3x2 experimental design that factored sequencing methods (independent variable 1; three levels) with level-bridging scaffolding (independent variable 2; two levels) and compared the effectiveness of each combination. The study measured two dependent variables: (1) knowledge integration (i.e., integrating and connecting content-specific normative concepts and providing coherent scientific explanations); (2) understanding of the deep causal structure (i.e., being able to grasp and transfer the causal knowledge of a complex system). The study used a computer-based simulation environment as the research platform to teach the ideal gas law as a system. The ideal gas law is an emergent chemical system that has three levels: (1) experiential macro level (EM) (e.g., an aerosol can explodes when it is thrown into the fire); (2) abstract macro level (AM) (i.e., the relationships among temperature, pressure and volume); (3) micro level (Mi) (i.e., molecular activity). The sequencing methods of these levels were manipulated by changing the order in which they were delivered with three possibilities: (1) EM-AM-Mi; (2) Mi-AM-EM; (3) AM-Mi-EM. The level-bridging scaffolding variable was manipulated on two aspects: (1) inserting inter-level questions among learning activities; (2) two simulations dynamically linked in the final learning activity. Addressing the first

  1. OPTIMIZATION OF THE HYSPEC DESIGN USING MONTE CARLO SIMULATIONS.

    SciTech Connect

    GHOSH, V.J.; HAGEN, M.E.; LEONHARDT, W.J.; ZALIZNYAK, I.; SHAPIRO, S.M.; PASSELL, L.

    2005-04-25

    HYSPEC is a direct geometry spectrometer to be installed at the SNS [1] on beamline 14B where it will view a cryogenic coupled hydrogen moderator, The ''hybrid'' design combines time-of-flight spectroscopy with focusing Bragg optics to provide a high monochromatic flux on small single crystal samples, with a very low background at an extended detector bank. The instrument is optimized for an incident energy range of 3-90meV. It will have a medium energy resolution (2-10%) and will provide a flux on sample of the order of 10{sup 6}-10{sup 7} neutrons/s-cm{sup 2}. The spectrometer will be located in a satellite building outside the SNS experimental hall at the end of a 35m curved supermirror guide. A straight-slotted Fermi chopper will be used to monochromate the neutron beam and to determine the burst width. The 15cm high, 4cm wide beam will be focused onto a 2cm by 2cm area at the sample position using Bragg reflection from one of two crystal arrays. For unpolarized neutron studies these will be Highly Oriented Pyrolitic graphite crystals while for polarized neutron studies these will be replaced with Heusler alloy crystals. These focusing crystal arrays will be placed in a drum shield similar to those used for triple axis spectrometers. Hyspec will have a movable detector bank housing 160 position sensitive detectors. This detector bank will pivot about the sample axis. It will have a radius of 4.5m, a horizontal range of 60{sup o}, and a vertical range of {+-} 7.5{sup o}. In order to reduce background at the detector bank both a curved guide and a T0 chopper will be used. A bank of 20 supermirror bender polarization analyzers [2] will be used to spatially separate the polarized neutrons in the scattered beam so that both scattered neutron spin states can be measured simultaneously. The results of Monte Carlo simulations performed to optimize the instrument design will be discussed.

  2. Rapidly Re-Configurable Flight Simulator Tools for Crew Vehicle Integration Research and Design

    NASA Technical Reports Server (NTRS)

    Pritchett, Amy R.

    2002-01-01

    While simulation is a valuable research and design tool, the time and difficulty required to create new simulations (or re-use existing simulations) often limits their application. This report describes the design of the software architecture for the Reconfigurable Flight Simulator (RFS), which provides a robust simulation framework that allows the simulator to fulfill multiple research and development goals. The core of the architecture provides the interface standards for simulation components, registers and initializes components, and handles the communication between simulation components. The simulation components are each a pre-compiled library 'plugin' module. This modularity allows independent development and sharing of individual simulation components. Additional interfaces can be provided through the use of Object Data/Method Extensions (OD/ME). RFS provides a programmable run-time environment for real-time access and manipulation, and has networking capabilities using the High Level Architecture (HLA).

  3. Rapidly Re-Configurable Flight Simulator Tools for Crew Vehicle Integration Research and Design

    NASA Technical Reports Server (NTRS)

    Schutte, Paul C.; Trujillo, Anna; Pritchett, Amy R.

    2000-01-01

    While simulation is a valuable research and design tool, the time and difficulty required to create new simulations (or re-use existing simulations) often limits their application. This report describes the design of the software architecture for the Reconfigurable Flight Simulator (RFS), which provides a robust simulation framework that allows the simulator to fulfill multiple research and development goals. The core of the architecture provides the interface standards for simulation components, registers and initializes components, and handles the communication between simulation components. The simulation components are each a pre-compiled library 'plug-in' module. This modularity allows independent development and sharing of individual simulation components. Additional interfaces can be provided through the use of Object Data/Method Extensions (OD/ME). RFS provides a programmable run-time environment for real-time access and manipulation, and has networking capabilities using the High Level Architecture (HLA).

  4. Improving the Aircraft Design Process Using Web-based Modeling and Simulation

    NASA Technical Reports Server (NTRS)

    Reed, John A.; Follen, Gregory J.; Afjeh, Abdollah A.

    2003-01-01

    Designing and developing new aircraft systems is time-consuming and expensive. Computational simulation is a promising means for reducing design cycle times, but requires a flexible software environment capable of integrating advanced multidisciplinary and muitifidelity analysis methods, dynamically managing data across heterogeneous computing platforms, and distributing computationally complex tasks. Web-based simulation, with its emphasis on collaborative composition of simulation models, distributed heterogeneous execution, and dynamic multimedia documentation, has the potential to meet these requirements. This paper outlines the current aircraft design process, highlighting its problems and complexities, and presents our vision of an aircraft design process using Web-based modeling and simulation.

  5. Improving the Aircraft Design Process Using Web-Based Modeling and Simulation

    NASA Technical Reports Server (NTRS)

    Reed, John A.; Follen, Gregory J.; Afjeh, Abdollah A.; Follen, Gregory J. (Technical Monitor)

    2000-01-01

    Designing and developing new aircraft systems is time-consuming and expensive. Computational simulation is a promising means for reducing design cycle times, but requires a flexible software environment capable of integrating advanced multidisciplinary and multifidelity analysis methods, dynamically managing data across heterogeneous computing platforms, and distributing computationally complex tasks. Web-based simulation, with its emphasis on collaborative composition of simulation models, distributed heterogeneous execution, and dynamic multimedia documentation, has the potential to meet these requirements. This paper outlines the current aircraft design process, highlighting its problems and complexities, and presents our vision of an aircraft design process using Web-based modeling and simulation.

  6. Nore1a drives Ras to flick the P53 senescence switch

    PubMed Central

    Donninger, Howard; Clark, Geoffrey J.

    2016-01-01

    ABSTRACT RAS-induced senescence is a protective mechanism to avoid unrestricted cell growth due to aberrant mitogenic signals; however, the exact mechanism by which RAS induces senescence is not known. We recently identified a novel pathway linking RAS to p53 via NORE1A and HIPK2 that mechanistically explains how Ras induces senescence. PMID:27314075

  7. Rapid Modeling, Assembly and Simulation in Design Optimization

    NASA Technical Reports Server (NTRS)

    Housner, Jerry

    1997-01-01

    A new capability for design is reviewed. This capability provides for rapid assembly of detail finite element models early in the design process where costs are most effectively impacted. This creates an engineering environment which enables comprehensive analysis and design optimization early in the design process. Graphical interactive computing makes it possible for the engineer to interact with the design while performing comprehensive design studies. This rapid assembly capability is enabled by the use of Interface Technology, to couple independently created models which can be archived and made accessible to the designer. Results are presented to demonstrate the capability.

  8. Women and the RAS: 100 years of Fellowship

    NASA Astrophysics Data System (ADS)

    Bailey, Mandy

    2016-02-01

    In January 1916, the RAS elected its first women Fellows. Mandy Bailey looks back at the social and scientific circumstances of this step towards equality, introducing a year of articles celebrating the centenary.

  9. A Study of Educational Simulations Part II--Interface Design

    ERIC Educational Resources Information Center

    Adams, W.; Reid, S.; LeMaster, R.; McKagan, S.; Perkins, K.; Dubson, M.; Wieman, C.

    2008-01-01

    Interactive computer simulations with complex representations and sophisticated graphics are a relatively new addition to the classroom, and research in this area is limited. We have conducted over 200 individual student interviews during which the students described what they were thinking as they interacted with simulations. These interviews…

  10. WRF model performance analysis for a suite of simulation design

    NASA Astrophysics Data System (ADS)

    Mohan, Manju; Sati, Ankur Prabhat

    2016-03-01

    At present scientists are successfully using Numerical Weather Prediction (NWP) models to achieve a reliable forecast. Nested domains are preferred by the modelling community with varying grid ratios having wider applications. The impact of the nesting grid ratio (NGR) on the model performance needs systematic analysis and explored in the present study. The usage of WRF is mostly as a mesoscale model in simulating either extreme events or events of smaller duration shown with statistical model evaluation for the correspondingly similar and short period of time. Thus, influence of the simulation period on model performance has been examined for key meteorological parameters. Several works done earlier on episodes involve model implementation for longer duration and for that single simulation is performed often for a continuous stretch. This study scrutinizes the influence on model performance due to one single simulation versus several smaller simulations for the same duration; essentially splitting the run-time. In the present study, the surface wind (i.e., winds at 10 meters), temperature and Relative humidity at 2 meters as obtained from model simulations are compared with the Observations. The sensitivity study of nesting grid ratio, continuous versus smaller split simulations and realistic simulation period is done in the present study. It is found that there is no statistically significant difference in the simulated results on changing the nesting grid ratio while the smaller time split schemes (2 days and 4 days schemes on comparison with 8 days and 16 days continuous run) improve the results significantly. The impact of increasing number of observations from different sites on model performance is also scrutinised. Furthermore, conceptual framework is provided for Optimum time period for simulations to have confidence in statistical model evaluation.

  11. Ras Homolog Enriched in Brain (Rheb) Enhances Apoptotic Signaling*

    PubMed Central

    Karassek, Sascha; Berghaus, Carsten; Schwarten, Melanie; Goemans, Christoph G.; Ohse, Nadine; Kock, Gerd; Jockers, Katharina; Neumann, Sebastian; Gottfried, Sebastian; Herrmann, Christian; Heumann, Rolf; Stoll, Raphael

    2010-01-01

    Rheb is a homolog of Ras GTPase that regulates cell growth, proliferation, and regeneration via mammalian target of rapamycin (mTOR). Because of the well established potential of activated Ras to promote survival, we sought to investigate the ability of Rheb signaling to phenocopy Ras. We found that overexpression of lipid-anchored Rheb enhanced the apoptotic effects induced by UV light, TNFα, or tunicamycin in an mTOR complex 1 (mTORC1)-dependent manner. Knocking down endogenous Rheb or applying rapamycin led to partial protection, identifying Rheb as a mediator of cell death. Ras and c-Raf kinase opposed the apoptotic effects induced by UV light or TNFα but did not prevent Rheb-mediated apoptosis. To gain structural insight into the signaling mechanisms, we determined the structure of Rheb-GDP by NMR. The complex adopts the typical canonical fold of RasGTPases and displays the characteristic GDP-dependent picosecond to nanosecond backbone dynamics of the switch I and switch II regions. NMR revealed Ras effector-like binding of activated Rheb to the c-Raf-Ras-binding domain (RBD), but the affinity was 1000-fold lower than the Ras/RBD interaction, suggesting a lack of functional interaction. shRNA-mediated knockdown of apoptosis signal-regulating kinase 1 (ASK-1) strongly reduced UV or TNFα-induced apoptosis and suppressed enhancement by Rheb overexpression. In conclusion, Rheb-mTOR activation not only promotes normal cell growth but also enhances apoptosis in response to diverse toxic stimuli via an ASK-1-mediated mechanism. Pharmacological regulation of the Rheb/mTORC1 pathway using rapamycin should take the presence of cellular stress into consideration, as this may have clinical implications. PMID:20685651

  12. Decoding RAS isoform and codon-specific signalling

    PubMed Central

    Newlaczyl, Anna U.; Hood, Fiona E.; Coulson, Judy M.; Prior, Ian A.

    2014-01-01

    RAS proteins are key signalling hubs that are oncogenically mutated in 30% of all cancer cases. Three genes encode almost identical isoforms that are ubiquitously expressed, but are not functionally redundant. The network responses associated with each isoform and individual oncogenic mutations remain to be fully characterized. In the present article, we review recent data defining the differences between the RAS isoforms and their most commonly mutated codons and discuss the underlying mechanisms. PMID:25109951

  13. Feasibility studies and pre-design simulation of Warsaw's new wastewater treatment plant.

    PubMed

    Oleszkiewicz, J A; Kalinowska, E; Dold, P; Barnard, J L; Bieniowski, M; Ferenc, Z; Jones, R; Rypina, A; Sudol, J

    2004-12-01

    The proposed transfer of wastewater from the western part of Warsaw, across the Wisla (Vistula) River for joint treatment at the existing eastern side "Czajka" wastewater treatment plant (WWTP) will result in combined winter flows of approx. 580,000 m3 d(-1). One-year of pilot-scale studies defined the COD characteristics and kinetics of nitrogen removal and VFA production from primary sludge. BioWin simulation was used to size and price the optional processes and pointed to the Westbank process as the most cost-effective. The process consists of a sequence of a RAS pre-denitrification zone followed by an anaerobic, anoxic and aerobic zone. Some 100-150 t d(-1) of 10% methanol would be needed to remove 2-4 mg l(-1) of NO3-N above the recommended effluent level TN = 10 mg l(-1). Applying the principle of annual average 80% TN removal, and allowing for use of daily composite samples (rather than grab) could annually save the municipality over 1.5 million Euro on external carbon source. PMID:15691201

  14. Plk2 Raps up Ras to subdue synapses

    PubMed Central

    Lee, Kea Joo; Hoe, Hyang-Sook

    2011-01-01

    We recently identified the activity-inducible protein kinase Plk2 as a novel overseer of the balance between Ras and Rap small GTPases. Plk2 achieves a profound level of regulatory control by interacting with and phosphorylating at least four Ras and Rap guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Combined, these actions result in synergistic suppression of Ras and hyperstimulation of Rap signaling. Perturbation of Plk2 function abolished homeostatic adaptation of synapses to enhanced activity and impaired behavioral adaptation in various learning tasks, indicating that this regulation was critical for maintaining appropriate Ras/Rap levels. These studies provide insights into the highly cooperative nature of Ras and Rap regulation in neurons. However, different GEF and GAP substrates of Plk2 also controlled specific aspects of dendritic spine morphology, illustrating the ability of individual GAPs/GEFs to assemble microdomains of Ras and Rap signaling that respond to different stimuli and couple to distinct output pathways. PMID:21776418

  15. Cooperative loss of RAS feedback regulation drives myeloid leukemognesis

    PubMed Central

    Zhao, Zhen; Chen, Chi-Chao; Rillahan, Cory D.; Shen, Ronglai; Kitzing, Thomas; McNerney, Megan E.; Diaz-Flores, Ernesto; Zuber, Johannes; Shannon, Kevin; Le Beau, Michelle M.; Spector, Mona S.; Kogan, Scott C.; Lowe, Scott W.

    2015-01-01

    RAS network activation is common in human cancers and, in acute myeloid leukemia (AML), achieved mainly through gain-of-function mutations in KRAS, NRAS, or the FLT3 receptor tyrosine kinase1. In mice, we show that premalignant myeloid cells harboring a KrasG12D allele retain low Ras signaling owing to a negative feedback involving Spry4 that prevents transformation. In humans, SPRY4 is located on chromosome 5q, a region affected by large heterozygous deletion that are associated with an aggressive disease in which gain-of-function RAS pathway mutations are rare. These 5q deletions often co-occur with chromosome 17 alterations involving deletion of NF1 - another RAS negative regulator - and TP53. Accordingly, combined suppression of Spry4, Nf1 and Trp53 produces high Ras signaling and drives AML in mice. Therefore, SPRY4 is a 5q tumor suppressor whose disruption contributes to a lethal AML subtype that appears to acquire RAS pathway activation through loss of negative regulators. PMID:25822087

  16. Ras and Rap Signaling in Synaptic Plasticity and Mental Disorders

    PubMed Central

    Stornetta, Ruth L.; Zhu, J. Julius

    2011-01-01

    The Ras family GTPases (Ras, Rap1, and Rap2) and their downstream mitogen-activated protein kinases (ERK, JNK, and p38MAPK) and PI3K signaling cascades control various physiological processes. In neuronal cells, recent studies have shown that these parallel cascades signal distinct forms of AMPA-sensitive glutamate receptor trafficking during experience-dependent synaptic plasticity and adaptive behavior. Interestingly, both hypo- and hyper-activation of Ras/Rap signaling impair the capacity of synaptic plasticity, underscoring the importance of a “happy-medium” dynamic regulation of the signaling. Moreover, accumulating reports have linked various genetic defects that either up- or down-regulate Ras/Rap signaling with a number of mental disorders associated with learning disability (e.g., Alzheimer’s disease, Angelman syndrome, autism, cardio-facio-cutaneous syndrome, Coffin-Lowry syndrome, Costello syndrome, Cowden and Bannayan-Riley-Ruvalcaba syndromes, fragile X syndrome, neurofibromatosis type 1, Noonan syndrome, schizophrenia, tuberous sclerosis, and X-linked mental retardation), highlighting the necessity of happy-medium dynamic regulation of Ras/Rap signaling in learning behavior. Thus, the recent advances in understanding of neuronal Ras/Rap signaling provide a useful guide for developing novel treatments for mental diseases. PMID:20431046

  17. Integrated design and simulation for millimeter-wave antenna systems

    NASA Technical Reports Server (NTRS)

    Cwik, T.; Katz, D. S.; Villegas, F. J.

    2000-01-01

    In this paper the development and application of MODTool (Millimeter-wave Optics Design), a design tool that efficiently integrates existing millimeter-wave optics design software with a solid body modeler and thermal/structural analysis packages, will be discussed.

  18. Design and simulation of latent heat storage units. Final report

    SciTech Connect

    Shamsundar, N.; Stein, E.; Rooz, E.; Bascaran, E.; Lee, T.C.

    1992-04-01

    This report presents the results of two years of research and development on passive latent heat storage systems. Analytical models have been developed and extended, and a computer code for simulating the performance of a latent heat storage has been developed. The code is intended to be merged into a larger solar energy system simulation code and used for making realistic system studies. Simulation studies using a code which has a flexible and accurate routine for handling the storage subsystem should lead to the development of better systems than those in which storage is added on after the rest of the system has already been selected and optimized.

  19. Design and simulation of latent heat storage units

    SciTech Connect

    Shamsundar, N.; Stein, E.; Rooz, E.; Bascaran, E.; Lee, T.C. )

    1992-04-01

    This report presents the results of two years of research and development on passive latent heat storage systems. Analytical models have been developed and extended, and a computer code for simulating the performance of a latent heat storage has been developed. The code is intended to be merged into a larger solar energy system simulation code and used for making realistic system studies. Simulation studies using a code which has a flexible and accurate routine for handling the storage subsystem should lead to the development of better systems than those in which storage is added on after the rest of the system has already been selected and optimized.

  20. Application of software simulation to DBS transmission design and evaluation

    NASA Astrophysics Data System (ADS)

    White, Lawrence W.; Palmer, Larry C.; Chang, Peter Y.; Shenoy, Ajit

    The paper describes software simulation results in the following three areas related to DBS planning: multipath and overdeviation of the video signal, digital audio transmission, and phase-locked loop demodulation. The results obtained for multipath and overdeviation involved simulation to examine a dual-path phenomenon that can be encountered in DBS applications. Results are also presented on the insertion of high rate digital data directly into the horizontal blanking interval of the video scan line. The results of simulations with a phase-locked demodular determined the degree of threshold extension achieved for various test patterns, as compared to a conventional limiter/discriminator.

  1. The Statistical Power of the Cluster Randomized Block Design with Matched Pairs--A Simulation Study

    ERIC Educational Resources Information Center

    Dong, Nianbo; Lipsey, Mark

    2010-01-01

    This study uses simulation techniques to examine the statistical power of the group- randomized design and the matched-pair (MP) randomized block design under various parameter combinations. Both nearest neighbor matching and random matching are used for the MP design. The power of each design for any parameter combination was calculated from…

  2. Simulation design: A Teaching Technique for Political Science

    ERIC Educational Resources Information Center

    Deiner, John T.

    1974-01-01

    Goals, course structure, physical and technical problems, the running of a simulation and evaluation of students are described for a game representing the political system of Argentina in a university comparative government course. (Author/KM)

  3. The F-92 RELIANT: Air transport system design simulation

    NASA Technical Reports Server (NTRS)

    1992-01-01

    The design proposal of a semester long design project by group 'F' for AE 441 is addressed. In formulating this design, the driving philosophy was not just to fulfill the mission requirements (discussed in chapter two), but to do so in a creative manner - this explains the unconventional aircraft design, named the F-92 RELIANT. Although unconventional, and perhaps more expensive to produce, the design has distinct advantages which could only be attained through such a creative design. Major components of the F-92 Reliant include: (1) unobstructed cargo bay, 1024 cu. in. capability; (2) loading ramp; (3) dual wing configuration; and (4) polyhedral wing configuration. These design components either originated or evolved to create an aircraft that would most effectively meet the goals of cargo transportation in AeroWorld at minimum cost.

  4. Early Design Choices: Capture, Model, Integrate, Analyze, Simulate

    NASA Technical Reports Server (NTRS)

    Malin, Jane T.

    2004-01-01

    I. Designs are constructed incrementally to meet requirements and solve problems: a) Requirements types: objectives, scenarios, constraints, ilities. etc. b) Problem/issue types: risk/safety, cost/difficulty, interaction, conflict, etc. II. Capture requirements, problems and solutions: a) Collect design and analysis products and make them accessible for integration and analysis; b) Link changes in design requirements, problems and solutions; and c) Harvest design data for design models and choice structures. III. System designs are constructed by multiple groups designing interacting subsystems a) Diverse problems, choice criteria, analysis methods and point solutions. IV. Support integration and global analysis of repercussions: a) System implications of point solutions; b) Broad analysis of interactions beyond totals of mass, cost, etc.

  5. Resistance of R-Ras knockout mice to skin tumour induction

    PubMed Central

    May, Ulrike; Prince, Stuart; Vähätupa, Maria; Laitinen, Anni M.; Nieminen, Katriina; Uusitalo-Järvinen, Hannele; Järvinen, Tero A. H.

    2015-01-01

    The R-ras gene encodes a small GTPase that is a member of the Ras family. Despite close sequence similarities, R-Ras is functionally distinct from the prototypic Ras proteins; no transformative activity and no activating mutations of R-Ras in human malignancies have been reported for it. R-Ras activity appears inhibitory towards tumour proliferation and invasion, and to promote cellular quiescence. Contrary to this, using mice with a deletion of the R-ras gene, we found that R-Ras facilitates DMBA/TPA-induced skin tumour induction. The tumours appeared in wild-type (WT) mice on average 6 weeks earlier than in R-Ras knockout (R-Ras KO) mice. WT mice developed almost 6 times more tumours than R-Ras KO mice. Despite strong R-Ras protein expression in the dermal blood vessels, no R-Ras could be detected in the epidermis from where the tumours arose. The DMBA/TPA skin tumourigenesis-model is highly dependent upon inflammation, and we found a greatly attenuated skin inflammatory response to DMBA/TPA-treatment in the R-Ras KO mice in the context of leukocyte infiltration and proinflammatory cytokine expression. Thus, these data suggest that despite its characterised role in promoting cellular quiescence, R-Ras is pro-tumourigenic in the DMBA/TPA tumour model and important for the inflammatory response to DMBA/TPA treatment. PMID:26133397

  6. The Design of an ITS-Based Business Simulation: A New Epistemology for Learning.

    ERIC Educational Resources Information Center

    Gold, Steven C.

    1998-01-01

    Discusses the design and use of intelligent tutoring systems (ITS) for computerized business simulations. Reviews the use of ITS as an instructional technology; presents a model for ITS-based business simulations; examines the user interface and link between the ITS and simulation; and recommends expert-consultant diagnostic testing, and…

  7. Challenges in Integrating a Complex Systems Computer Simulation in Class: An Educational Design Research

    ERIC Educational Resources Information Center

    Loke, Swee-Kin; Al-Sallami, Hesham S.; Wright, Daniel F. B.; McDonald, Jenny; Jadhav, Sheetal; Duffull, Stephen B.

    2012-01-01

    Complex systems are typically difficult for students to understand and computer simulations offer a promising way forward. However, integrating such simulations into conventional classes presents numerous challenges. Framed within an educational design research, we studied the use of an in-house built simulation of the coagulation network in four…

  8. Optical design of a high-power LED-based solar simulator

    NASA Astrophysics Data System (ADS)

    Toro-Betancur, Veronica; Velásquez-López, Alejandro; Velásquez, David; Acevedo-Gómez, David

    2016-04-01

    The optical design of a High-Power LED based Solar Simulator was made in order to reach the AM1.5G spectrum standards. An optical model of the light emitted by the LEDs was made and used for spectral intensities calculations and the light intensity uniformity was optimized. A class AAA solar simulator was designed using a hexagonal LED distribution.

  9. Ideas in Practice (3): A Simulated Laboratory Experience in Digital Design.

    ERIC Educational Resources Information Center

    Cleaver, Thomas G.

    1988-01-01

    Gives an example of the use of a simplified logic simulator in a logic design course. Discusses some problems in logic design classes, commercially available software, and software problems. Describes computer-aided engineering (CAE) software. Lists 14 experiments in the simulated laboratory and presents students' evaluation of the course. (YP)

  10. The Use of Simulation for the Design and Analysis of Thermophotovoltaic Networks

    SciTech Connect

    JE Oppenlander; JL Vell; WS Gaes; DM Siganporia; LR Danielson; MW Dashiell

    2004-07-20

    Simulation has provided valuable quantification of the fundamental behavior of thermophotovoltaic cell networks. The results of simulation studies have supported the design and fabrication of small-scale demonstration networks and are expected to guide assembly of large-scale systems. This paper describes the methodology and software simulator developed to address issues in thermophotovoltaic (TPV) networking, including failure analysis, electrical network design, and nonuniform illumination. Results from simulation studies are given illustrating their application to the design and fabrication of small-scale TPV arrays.

  11. Pharmacological modulation of oncogenic Ras by natural products and their derivatives: Renewed hope in the discovery of novel anti-Ras drugs.

    PubMed

    Quah, Shun Ying; Tan, Michelle Siying; Teh, Yuan Han; Stanslas, Johnson

    2016-06-01

    Oncogenic rat sarcoma (Ras) is linked to the most fatal cancers such as those of the pancreas, colon, and lung. Decades of research to discover an efficacious drug that can block oncogenic Ras signaling have yielded disappointing results; thus, Ras was considered "undruggable" until recently. Inhibitors that directly target Ras by binding to previously undiscovered pockets have been recently identified. Some of these molecules are either isolated from natural products or derived from natural compounds. In this review, we described the potential of these compounds and other inhibitors of Ras signaling in drugging Ras. We highlighted the modes of action of these compounds in suppressing signaling pathways activated by oncogenic Ras, such as mitogen-activated protein kinase (MAPK) signaling and the phosphoinositide-3-kinase (PI3K) pathways. The anti-Ras strategy of these compounds can be categorized into four main types: inhibition of Ras-effector interaction, interference of Ras membrane association, prevention of Ras-guanosine triphosphate (GTP) formation, and downregulation of Ras proteins. Another promising strategy that must be validated experimentally is enhancement of the intrinsic Ras-guanosine triphosphatase (GTPase) activity by small chemical entities. Among the inhibitors of Ras signaling that were reported thus far, salirasib and TLN-4601 have been tested for their clinical efficacy. Although both compounds passed phase I trials, they failed in their respective phase II trials. Therefore, new compounds of natural origin with relevant clinical activity against Ras-driven malignancies are urgently needed. Apart from salirasib and TLN-4601, some other compounds with a proven inhibitory effect on Ras signaling include derivatives of salirasib, sulindac, polyamine, andrographolide, lipstatin, levoglucosenone, rasfonin, and quercetin. PMID:27016467

  12. A novel Ras GTPase (Ras3) regulates conidiation, multi-stress tolerance and virulence by acting upstream of Hog1 signaling pathway in Beauveria bassiana.

    PubMed

    Guan, Yi; Wang, Ding-Yi; Ying, Sheng-Hua; Feng, Ming-Guang

    2015-09-01

    Two Ras ATPases (Ras1 and Ras2) are well known to regulate antagonistically or cooperatively various cellular events in many fungi. Here we show the significance of a novel Ras homolog (Ras3) for Beauveria bassiana. Ras3 possesses five domains and two GTP/GDP switches typical for Ras family and was proven to localize to plasma membrane despite the position change of a membrane-targeting cysteine in C-terminal CAAX motif. Deletion of ras3 altered temporal transcription pattern of ras1 instead of ras2. Compared with wild-type, Δras3 grew significantly faster in a rich medium but slower in some minimal media, and produced far fewer conidia with impaired quality, which was evident with slower germination, attenuated virulence, reduced thermotolerance and decreased UV-B resistance. Moreover, Δras3 was much more sensitive to the oxidative stress of menadione than of H2O2 and to the stress of high osmolarity than of cell wall perturbation during growth. The high sensitivity of Δras3 to menadione was concurrent with reductions in both gene transcripts and total activity of superoxide dismutases. Intriguingly, the high osmosensitivity was concurrent with not only reduced transcripts of a critical transcription factor (Msn2) and most signaling proteins in the high-osmolarity-glycerol pathway of Δras3 but nearly undetectable phosphorylation signal of Hog1 hallmarking the pathway. All the changes were restored by ras3 complementation. Taken together, Ras3 is involved in the Hog1 pathway required for osmoregulation and hence can positively regulate conidiation, germination, multi-stress tolerance and virulence linked to the biological control potential of the filamentous insect pathogen. PMID:26162967

  13. A method motion simulator design based on modeling characteristics of the human operator

    NASA Technical Reports Server (NTRS)

    Repperger, D. W.; Junker, A. M.

    1978-01-01

    A design criteria is obtained to compare two simulators and evaluate their equivalence or credibility. In the subsequent analysis the comparison of two simulators can be considered as the same problem as the comparison of a real world situation and a simulation's representation of this real world situation. The design criteria developed involves modeling of the human operator and defining simple parameters to describe his behavior in the simulator and in the real world situation. In the process of obtaining human operator parameters to define characteristics to evaluate simulators, measures are also obtained on these human operator characteristics which can be used to describe the human as an information processor and controller. First, a study is conducted on the simulator design problem in such a manner that this modeling approach can be used to develop a criteria for the comparison of two simulators.

  14. Advancing lighting and daylighting simulation: The transition from analysis to design aid tools

    SciTech Connect

    Hitchcock, R.J.

    1995-05-01

    This paper explores three significant software development requirements for making the transition from stand-alone lighting simulation/analysis tools to simulation-based design aid tools. These requirements include specialized lighting simulation engines, facilitated methods for creating detailed simulatable building descriptions, an automated techniques for providing lighting design guidance. Initial computer implementations meant to address each of these requirements are discussed to further elaborate these requirements and to illustrate work-in-progress.

  15. Regulation of an H-ras-related transcript by parathyroid hormone in rat osteosarcoma cells

    NASA Technical Reports Server (NTRS)

    Scott, D. K.; Weaver, W. R.; Clohisy, J. C.; Brakenhoff, K. D.; Kahn, A. J.; Partridge, N. C.

    1992-01-01

    The rat osteosarcoma cell line UMR 106-01 is a commonly used model system for the study of osteoblast function. However, it also expresses a phenotype characteristic of transformed cells. To test whether the latter could be accounted for by aberrant oncogene expression, we probed Northern blots of UMR and other osteoblastic cells with a panel of oncogene probes. These blots, when probed with a cDNA specific for v-H-ras, revealed a 7.0-kilobase (kb) H-ras-related transcript (designated HRRT) in UMR 106-01 cells that was not expressed in other osteoblastic cells. Osteoblast-enriched calvarial cells expressed the typical 1.1-kb H-ras mRNA, which was absent in UMR cells. Additionally, Western blots of lysates of UMR cells documented the presence of three proteins immunologically related to H-rasp21. To determine whether HRRT represented a recombinant retrovirus product, Northern blots were probed with a cDNA specific for the highly conserved gag-pol region of Moloney murine leukemia virus. These blots showed parallel cross-reactivity with an apparently identical transcript of 7.0 kb. The 7.0-kb transcripts detected by both v-H-ras and gag-pol probes declined to the same extent after treatment with concentrations of PTH known to inhibit proliferation of these cells. PTH regulated the abundance of HRRT in a time- and dose-dependent manner, with greatest repression of the transcript after 8 h of treatment with 10(-8) M PTH. The decrease in HRRT could not be completely accounted for by changes in transcriptional activity, as determined by nuclear run-on assays.(ABSTRACT TRUNCATED AT 250 WORDS).

  16. Integrated Simulation Design Challenges to Support TPS Repair Operations

    NASA Technical Reports Server (NTRS)

    Quiocho, Leslie J.; Crues, Edwin Z.; Huynh, An; Nguyen, Hung T.; MacLean, John

    2006-01-01

    During the Orbiter Repair Maneuver (OM) operations planned for Return to Flight (RTF), the Shuttle Remote Manipulator System (SRMS) must grapple the International Space Station (ISS), undock the Orbiter, maneuver it through a long duration trajectory, and orient it to an EVA crewman poised at the end of the Space Station Remote Manipulator System (SSRMS) to facilitate the repair of the Thermal Protection System (TPS). Once repair has been completed and confirmed, then the SRMS proceeds back through the trajectory to dock the Orbiter to the Orbiter Docking System. In order to support analysis of the complex dynamic interactions of the integrated system formed by the Orbiter, ISS, SRMS, and SSMS during the ORM, simulation tools used for previous nominal mission support required substantial enhancements. These upgrades were necessary to provide analysts with the capabilities needed to study integrated system performance. Prevalent throughout this ORM operation is a dynamically varying topology. In other words, the ORM starts with the SRMS grappled to the mated Shuttle/ISS stack (closed loop topology), moves to an open loop chain topology consisting of the Shuttle, SRMS, and ISS, and then, at the repair configuration, extends the chain topology to one consisting of the Shuttle, SMS, ISS, and SSRMS/EVA crewman. The resulting long dynamic chain of vehicles and manipulators may exhibit significant motion between the Shuttle worksite and the EVA crewman due to the system flexibility throughout the topology (particularly within the SRMS/SSRMS joints and links). Since the attachment points of both manipulators span the flexible structure of the ISS, simulation analysis may also need to take that into consideration. Moreover, due to the lengthy time duration associated with the maneuver and repair, orbital effects become a factor and require the ISS vehicle control system to maintain active attitude control. Several facets of the ORM operation make the associated analytical

  17. Novel force resolver designs for a haptic surgery simulator.

    PubMed

    Zivanovic, Aleksandar; Dibble, Edward; Davies, Brian

    2004-01-01

    This paper presents the results of an investigation into the design of low cost, four degree of freedom force/torque resolvers for use in compact haptic devices for surgical training. Two designs using piezo-resistive sensors are described and one using strain gauges. The advantages and disadvantages of each approach are stated and conclusions presented. PMID:15544320

  18. The Significance of Ras Activity in Pancreatic Cancer Initiation

    PubMed Central

    Logsdon, Craig D.; Lu, Weiqin

    2016-01-01

    The genetic landscape of pancreatic cancer shows nearly ubiquitous mutations of K-RAS. However, oncogenic K-Rasmt alone is not sufficient to lead to pancreatic ductal adenocarcinoma (PDAC) in either human or in genetically modified adult mouse models. Many stimulants, such as high fat diet, CCK, LPS, PGE2 and others, have physiological effects at low concentrations that are mediated in part through modest increases in K-Ras activity. However, at high concentrations, they induce inflammation that, in the presence of oncogenic K-Ras expression, substantially accelerates PDAC formation. The mechanism involves increased activity of oncogenic K-Rasmt. Unlike what has been proposed in the standard paradigm for the role of Ras in oncogenesis, oncogenic K-Rasmt is now known to not be constitutively active. Rather, it can be activated by standard mechanisms similar to wild-type K-Ras, but its activity is sustained for a prolonged period. Furthermore, if the level of K-Ras activity exceeds a threshold at which it begins to generate its own activators, then a feed-forward loop is formed between K-Ras activity and inflammation and pathological processes including oncogenesis are initiated. Oncogenic K-Rasmt activation, a key event in PDAC initiation and development, is subject to complex regulatory mechanisms. Reagents which inhibit inflammation, such as the Cox2 inhibitor celecoxib, block the feed-forward loop and prevent induction of PDAC in models with endogenous oncogenic K-Rasmt. Increased understanding of the role of activating and inhibitory mechanisms on oncogenic K-Rasmt activity is of paramount importance for the development of preventive and therapeutic strategies to fight against this lethal disease. PMID:26929740

  19. Specific Conformational States of Ras GTPase upon Effector Binding

    PubMed Central

    2012-01-01

    To uncover the structural and dynamical determinants involved in the highly specific binding of Ras GTPase to its effectors, the conformational states of Ras in uncomplexed form and complexed to the downstream effectors Byr2, PI3Kγ, PLCε, and RalGDS were investigated using molecular dynamics and cross-comparison of the trajectories. The subtle changes in the dynamics and conformations of Ras upon effector binding require an analysis that targets local changes independent of global motions. Using a structural alphabet, a computational procedure is proposed to quantify local conformational changes. Positions detected by this approach were characterized as either specific for a particular effector, specific for an effector domain type, or as effector unspecific. A set of nine structurally connected residues (Ras residues 5–8, 32–35, 39–42, 55–59, 73–78, and 161–165), which link the effector binding site to the distant C-terminus, changed dynamics upon effector binding, indicating a potential effector-unspecific signaling route within the Ras structure. Additional conformational changes were detected along the N-terminus of the central β-sheet. Besides the Ras residues at the effector interface (e.g., D33, E37, D38, and Y40), which adopt effector-specific local conformations, the binding signal propagates from the interface to distant hot-spot residues, in particular to Y5 and D57. The results of this study reveal possible conformational mechanisms for the stabilization of the active state of Ras upon downstream effector binding and for the structural determinants responsible for effector specificity. PMID:23316125

  20. Knowledge-Driven Design of Virtual Patient Simulations

    ERIC Educational Resources Information Center

    Vergara, Victor; Caudell, Thomas; Goldsmith, Timothy; Panaiotis; Alverson, Dale

    2009-01-01

    Virtual worlds provide unique opportunities for instructors to promote, study, and evaluate student learning and comprehension. In this article, Victor Vergara, Thomas Caudell, Timothy Goldsmith, Panaiotis, and Dale Alverson explore the advantages of using virtual reality environments to create simulations for medical students. Virtual simulations…

  1. Detectors for the Superconducting Super Collider, design concepts, and simulation

    SciTech Connect

    Gabriel, T.A.

    1989-01-01

    The physics of compensation calorimetry is reviewed in the light of the need of the Superconducting Super Collider (SSC) detectors. The four major detector types: liquid argon, scintillator, room temperature liquids, and silicon, are analyzed with respect to some of their strengths and weaknesses. Finally, general comments are presented which reflect the reliability of simulation code systems. 29 refs., 20 figs., 6 tabs.

  2. Designing Better Scaffolding in Teaching Complex Systems with Graphical Simulations

    ERIC Educational Resources Information Center

    Li, Na

    2013-01-01

    Complex systems are an important topic in science education today, but they are usually difficult for secondary-level students to learn. Although graphic simulations have many advantages in teaching complex systems, scaffolding is a critical factor for effective learning. This dissertation study was conducted around two complementary research…

  3. Designing Simulations for Athletic Training Students through Interprofessional Teaching Collaboration

    ERIC Educational Resources Information Center

    Tivener, Kristin Ann; Gloe, Donna Sue

    2015-01-01

    Context: While multidisciplinary team approaches to education and practice have been promoted for decades, literature on collaborative efforts in athletic training and nursing remains sparse. Objective: The goal of this article is to provide an example of an interprofessional teaching collaboration in which a simulation scenario was developed…

  4. Aiding Design of Wave Energy Converters via Computational Simulations

    NASA Astrophysics Data System (ADS)

    Jebeli Aqdam, Hejar; Ahmadi, Babak; Raessi, Mehdi; Tootkaboni, Mazdak

    2015-11-01

    With the increasing interest in renewable energy sources, wave energy converters will continue to gain attention as a viable alternative to current electricity production methods. It is therefore crucial to develop computational tools for the design and analysis of wave energy converters. A successful design requires balance between the design performance and cost. Here an analytical solution is used for the approximate analysis of interactions between a flap-type wave energy converter (WEC) and waves. The method is verified using other flow solvers and experimental test cases. Then the model is used in conjunction with a powerful heuristic optimization engine, Charged System Search (CSS) to explore the WEC design space. CSS is inspired by charged particles behavior. It searches the design space by considering candidate answers as charged particles and moving them based on the Coulomb's laws of electrostatics and Newton's laws of motion to find the global optimum. Finally the impacts of changes in different design parameters on the power takeout of the superior WEC designs are investigated. National Science Foundation, CBET-1236462.

  5. Renewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis?

    PubMed

    Repasky, Gretchen A; Chenette, Emily J; Der, Channing J

    2004-11-01

    Ras proteins function as signal transducers and are mutationally activated in many human cancers. In 1993, Raf was identified as a key downstream effector of Ras signaling, and it was believed then that the primary function of Ras was simply to facilitate Raf activation. However, the subsequent discovery of other proteins that are effectors of Ras function suggested that oncogenic activities of Ras are mediated by both Raf-dependent and Raf-independent signaling. Further complexity arose with the identification of Ras effectors with putative tumor suppressor, rather than oncogenic, functions. However, the recent identification of B-raf mutations in human cancers has renewed the debate regarding whether Raf activation alone promotes Ras-mediated oncogenesis. In this article, we summarize the current knowledge of the contribution of Ras effectors in Ras-mediated oncogenesis. PMID:15519853

  6. High Altitude Venus Operations Concept Trajectory Design, Modeling and Simulation

    NASA Technical Reports Server (NTRS)

    Lugo, Rafael A.; Ozoroski, Thomas A.; Van Norman, John W.; Arney, Dale C.; Dec, John A.; Jones, Christopher A.; Zumwalt, Carlie H.

    2015-01-01

    A trajectory design and analysis that describes aerocapture, entry, descent, and inflation of manned and unmanned High Altitude Venus Operation Concept (HAVOC) lighter-than-air missions is presented. Mission motivation, concept of operations, and notional entry vehicle designs are presented. The initial trajectory design space is analyzed and discussed before investigating specific trajectories that are deemed representative of a feasible Venus mission. Under the project assumptions, while the high-mass crewed mission will require further research into aerodynamic decelerator technology, it was determined that the unmanned robotic mission is feasible using current technology.

  7. Conceptual Design and Numerical Simulations of Hypersonic Waverider Vehicle

    NASA Astrophysics Data System (ADS)

    Cao, D. Y.; Zhang, J. B.; Lee, C. H.

    A modularized airframe/propulsion integrated model is established by oblique shock wave theory, engineering method and method of characteristics(MOC). Based on this method, a new design methodology for hypersonic waverider vehicle which integrated scramjets with waverider airframe derived from cone-wedge flow field is presented. Integrated aero-propulsion performance of the waverider vehicle under on-design and off-design conditions is predicted using Euler equations discretized by Harten-Yee non-MUSCL TVD scheme and the combustor flow field is approximated by a quasi-ID cycle analysis, skin friction of vehicle is calculated by reference temperature method.

  8. A virtual simulator designed for collision prevention in proton therapy

    SciTech Connect

    Jung, Hyunuk; Kum, Oyeon; Han, Youngyih Park, Hee Chul; Kim, Jin Sung; Choi, Doo Ho

    2015-10-15

    Purpose: In proton therapy, collisions between the patient and nozzle potentially occur because of the large nozzle structure and efforts to minimize the air gap. Thus, software was developed to predict such collisions between the nozzle and patient using treatment virtual simulation. Methods: Three-dimensional (3D) modeling of a gantry inner-floor, nozzle, and robotic-couch was performed using SolidWorks based on the manufacturer’s machine data. To obtain patient body information, a 3D-scanner was utilized right before CT scanning. Using the acquired images, a 3D-image of the patient’s body contour was reconstructed. The accuracy of the image was confirmed against the CT image of a humanoid phantom. The machine components and the virtual patient were combined on the treatment-room coordinate system, resulting in a virtual simulator. The simulator simulated the motion of its components such as rotation and translation of the gantry, nozzle, and couch in real scale. A collision, if any, was examined both in static and dynamic modes. The static mode assessed collisions only at fixed positions of the machine’s components, while the dynamic mode operated any time a component was in motion. A collision was identified if any voxels of two components, e.g., the nozzle and the patient or couch, overlapped when calculating volume locations. The event and collision point were visualized, and collision volumes were reported. Results: All components were successfully assembled, and the motions were accurately controlled. The 3D-shape of the phantom agreed with CT images within a deviation of 2 mm. Collision situations were simulated within minutes, and the results were displayed and reported. Conclusions: The developed software will be useful in improving patient safety and clinical efficiency of proton therapy.

  9. Involvement of Ras in survival responsiveness to nitric oxide toxicity in pheochromocytoma cells.

    PubMed

    Jeong, Hyun Sik; Kim, Seong Won; Baek, Kwang Jin; Lee, Hee Sung; Kwon, Nyoun Soo; Kim, Young-Myeong; Yun, Hye-Young

    2002-11-01

    Nitric oxide (NO) plays a key role in attenuation of tumor growth by activated macrophages that generate large amount of cytotoxic/cytostatic free radicals. However, some tumor cells may survive from NO cytotoxicity and continue to proliferate to malignant tumors. Since a protooncogene product Ras was shown to be activated by NO, this study investigated the involvement of Ras in the cell survival in response to NO cytotoxicity in pheochromocytoma (PC12) cells. Treatment with Ras inhibitor or constitutive expression of dominant negative Ras markedly increased NO-induced cell death. NO-resistant PC12 cells (PC12-NO-R) exhibited higher steady state Ras activity than the parental PC12 cells. Inducible expression using tetracycline-on (Tet-on) system of Ras mutants (dominant negative Ras or dominant active Ras) demonstrated that blockade of Ras activity increased NO-induced cell death whereas enhancement of Ras activity attenuated NO-induced cell death. Furthermore, inducible expression of NO-insensitive mutant Ras selectively increased cellular vulnerability to NO but not to ROS. NO, Ras inhibitor and extracellular signal-regulated kinase (Erk) blocker synergistically increased cell death. These observations suggest that Ras activity may be a critical factor for survival response of tumor cells to NO toxicity and pharmacological agents affecting Ras activity may enhance efficacy of NO-mediated tumor therapies. PMID:12635656

  10. Signal Integration by Lipid-Mediated Spatial Cross Talk between Ras Nanoclusters

    PubMed Central

    Zhou, Yong; Liang, Hong; Rodkey, Travis; Ariotti, Nicholas; Parton, Robert G.

    2014-01-01

    Lipid-anchored Ras GTPases form transient, spatially segregated nanoclusters on the plasma membrane that are essential for high-fidelity signal transmission. The lipid composition of Ras nanoclusters, however, has not previously been investigated. High-resolution spatial mapping shows that different Ras nanoclusters have distinct lipid compositions, indicating that Ras proteins engage in isoform-selective lipid sorting and accounting for different signal outputs from different Ras isoforms. Phosphatidylserine is a common constituent of all Ras nanoclusters but is only an obligate structural component of K-Ras nanoclusters. Segregation of K-Ras and H-Ras into spatially and compositionally distinct lipid assemblies is exquisitely sensitive to plasma membrane phosphatidylserine levels. Phosphatidylserine spatial organization is also modified by Ras nanocluster formation. In consequence, Ras nanoclusters engage in remote lipid-mediated communication, whereby activated H-Ras disrupts the assembly and operation of spatially segregated K-Ras nanoclusters. Computational modeling and experimentation reveal that complex effects of caveolin and cortical actin on Ras nanoclustering are similarly mediated through regulation of phosphatidylserine spatiotemporal dynamics. We conclude that phosphatidylserine maintains the lateral segregation of diverse lipid-based assemblies on the plasma membrane and that lateral connectivity between spatially remote lipid assemblies offers important previously unexplored opportunities for signal integration and signal processing. PMID:24366544

  11. High-Alpha Research Vehicle (HARV) longitudinal controller: Design, analyses, and simulation resultss

    NASA Technical Reports Server (NTRS)

    Ostroff, Aaron J.; Hoffler, Keith D.; Proffitt, Melissa S.; Brown, Philip W.; Phillips, Michael R.; Rivers, Robert A.; Messina, Michael D.; Carzoo, Susan W.; Bacon, Barton J.; Foster, John F.

    1994-01-01

    This paper describes the design, analysis, and nonlinear simulation results (batch and piloted) for a longitudinal controller which is scheduled to be flight-tested on the High-Alpha Research Vehicle (HARV). The HARV is an F-18 airplane modified for and equipped with multi-axis thrust vectoring. The paper includes a description of the facilities, a detailed review of the feedback controller design, linear analysis results of the feedback controller, a description of the feed-forward controller design, nonlinear batch simulation results, and piloted simulation results. Batch simulation results include maximum pitch stick agility responses, angle of attack alpha captures, and alpha regulation for full lateral stick rolls at several alpha's. Piloted simulation results include task descriptions for several types of maneuvers, task guidelines, the corresponding Cooper-Harper ratings from three test pilots, and some pilot comments. The ratings show that desirable criteria are achieved for almost all of the piloted simulation tasks.

  12. Thermal simulation and design optimization of a thermopile infrared detector with an SU-8 membrane

    NASA Astrophysics Data System (ADS)

    Mattsson, C. G.; Bertilsson, K.; Thungström, G.; Nilsson, H.-E.; Martin, H.

    2009-05-01

    Simulation and optimization tools are commonly used in the design phase of advanced electronics devices. In this work, we present a thermal simulation and design optimization tool for infrared thermopile detectors based on a closed membrane structure. The tool can be used to simulate and optimize thermopile detectors with an arbitrary number of design parameters. The optimization utilizes the Nelder-Mead and the adaptive simulated annealing optimization algorithms to maximize the system performance. A thermopile detector with an SU-8-based closed membrane and metal-metal thermocouples has been simulated and optimized. Based on the results generated by the tool, an optimized detector has been fabricated and characterized. The results from the measurements presented are in good agreement with the simulation results.

  13. High Sensitivity MEMS Strain Sensor: Design and Simulation

    PubMed Central

    Mohammed, Ahmed A. S.; Moussa, Walied A.; Lou, Edmond

    2008-01-01

    In this article, we report on the new design of a miniaturized strain microsensor. The proposed sensor utilizes the piezoresistive properties of doped single crystal silicon. Employing the Micro Electro Mechanical Systems (MEMS) technology, high sensor sensitivities and resolutions have been achieved. The current sensor design employs different levels of signal amplifications. These amplifications include geometric, material and electronic levels. The sensor and the electronic circuits can be integrated on a single chip, and packaged as a small functional unit. The sensor converts input strain to resistance change, which can be transformed to bridge imbalance voltage. An analog output that demonstrates high sensitivity (0.03mV/με), high absolute resolution (1με) and low power consumption (100μA) with a maximum range of ±4000με has been reported. These performance characteristics have been achieved with high signal stability over a wide temperature range (±50°C), which introduces the proposed MEMS strain sensor as a strong candidate for wireless strain sensing applications under harsh environmental conditions. Moreover, this sensor has been designed, verified and can be easily modified to measure other values such as force, torque…etc. In this work, the sensor design is achieved using Finite Element Method (FEM) with the application of the piezoresistivity theory. This design process and the microfabrication process flow to prototype the design have been presented.

  14. Advanced Information Technology in Simulation Based Life Cycle Design

    NASA Technical Reports Server (NTRS)

    Renaud, John E.

    2003-01-01

    In this research a Collaborative Optimization (CO) approach for multidisciplinary systems design is used to develop a decision based design framework for non-deterministic optimization. To date CO strategies have been developed for use in application to deterministic systems design problems. In this research the decision based design (DBD) framework proposed by Hazelrigg is modified for use in a collaborative optimization framework. The Hazelrigg framework as originally proposed provides a single level optimization strategy that combines engineering decisions with business decisions in a single level optimization. By transforming this framework for use in collaborative optimization one can decompose the business and engineering decision making processes. In the new multilevel framework of Decision Based Collaborative Optimization (DBCO) the business decisions are made at the system level. These business decisions result in a set of engineering performance targets that disciplinary engineering design teams seek to satisfy as part of subspace optimizations. The Decision Based Collaborative Optimization framework more accurately models the existing relationship between business and engineering in multidisciplinary systems design.

  15. A methodology towards virtualisation-based high performance simulation platform supporting multidisciplinary design of complex products

    NASA Astrophysics Data System (ADS)

    Ren, Lei; Zhang, Lin; Tao, Fei; (Luke) Zhang, Xiaolong; Luo, Yongliang; Zhang, Yabin

    2012-08-01

    Multidisciplinary design of complex products leads to an increasing demand for high performance simulation (HPS) platforms. One great challenge is how to achieve high efficient utilisation of large-scale simulation resources in distributed and heterogeneous environments. This article reports a virtualisation-based methodology to realise a HPS platform. This research is driven by the issues concerning large-scale simulation resources deployment and complex simulation environment construction, efficient and transparent utilisation of fine-grained simulation resources and high reliable simulation with fault tolerance. A framework of virtualisation-based simulation platform (VSIM) is first proposed. Then the article investigates and discusses key approaches in VSIM, including simulation resources modelling, a method to automatically deploying simulation resources for dynamic construction of system environment, and a live migration mechanism in case of faults in run-time simulation. Furthermore, the proposed methodology is applied to a multidisciplinary design system for aircraft virtual prototyping and some experiments are conducted. The experimental results show that the proposed methodology can (1) significantly improve the utilisation of fine-grained simulation resources, (2) result in a great reduction in deployment time and an increased flexibility for simulation environment construction and (3)achieve fault tolerant simulation.

  16. Constraining Particle Variation in Lunar Regolith for Simulant Design

    NASA Technical Reports Server (NTRS)

    Schrader, Christian M.; Rickman, Doug; Stoeser, Douglas; Hoelzer, Hans

    2008-01-01

    Simulants are used by the lunar engineering community to develop and test technologies for In Situ Resource Utilization (ISRU), excavation and drilling, and for mitigation of hazards to machinery and human health. Working with the United States Geological Survey (USGS), other NASA centers, private industry and academia, Marshall Space Flight Center (MSFC) is leading NASA s lunar regolith simulant program. There are two main efforts: simulant production and simulant evaluation. This work requires a highly detailed understanding of regolith particle type, size, and shape distribution, and of bulk density. The project has developed Figure of Merit (FoM) algorithms to quantitatively compare these characteristics between two materials. The FoM can be used to compare two lunar regolith samples, regolith to simulant, or two parcels of simulant. In work presented here, we use the FoM algorithm to examine the variance of particle type in Apollo 16 highlands regolith core and surface samples. For this analysis we have used internally consistent particle type data for the 90-150 m fraction of Apollo core 64001/64002 from station 4, core 60009/60010 from station 10, and surface samples from various Apollo 16 stations. We calculate mean modal compositions for each core and for the group of surface samples and quantitatively compare samples of each group to its mean as a measurement of within-group variance; we also calculate an FoM for every sample against the mean composition of 64001/64002. This gives variation with depth at two locations and between Apollo 16 stations. Of the tested groups, core 60009/60010 has the highest internal variance with an average FoM score of 0.76 and core 64001/64002 has the lowest with an average FoM of 0.92. The surface samples have a low but intermediate internal variance with an average FoM of 0.79. FoM s calculated against the 64001/64002 mean reference composition range from 0.79-0.97 for 64001/64002, from 0.41-0.91 for 60009/60010, and from

  17. The design and operation of a planet emitted and albedo radiation simulator

    NASA Technical Reports Server (NTRS)

    Sweet, G. E.; Taylor, J. T.; Abbott, I. H. A.

    1972-01-01

    A simulator is described, which provides a dynamic simulation of planetary albedo and planet-emitted thermal radiation. The simulator was designed for model tests of advanced thermal control concepts, the development of space hardware, and flight qualification of small payloads. The simulator was designed to be used in a vacuum chamber equipped with liquid nitrogen cold walls and a solar simulator. The simulator consists of two major components: a gimbaled model support system and an array of quartz infrared lamps. Tests indicate that the apparatus will satisfactorily simulate the secondary radiation on a 0.92-meter spherical body in near-earth orbits. Calculations indicate that other shapes can be accommodated without structural modifications.

  18. Three dimensional projection environment for molecular design and surgical simulation.

    PubMed

    Wickstrom, Eric; Chen, Chang-Po; Devadhas, Devakumar; Wampole, Matthew; Jin, Yuan-Yuan; Sanders, Jeffrey M; Kairys, John C; Ankeny, Martha L; Hu, Rui; Barner, Kenneth E; Steiner, Karl V; Thakur, Mathew L

    2011-01-01

    We are developing agents for positron emission tomography (PET) imaging of cancer gene mRNA expression and software to fuse mRNA PET images with anatomical computerized tomography (CT) images to enable volumetric (3D) haptic (touch-and-feel) simulation of pancreatic cancer and surrounding organs prior to surgery in a particular patient. We have identified a novel ligand specific for epidermal growth factor receptor (EGFR) to direct PET agent uptake specifically into cancer cells, and created a volumetric haptic surgical simulation of human pancreatic cancer reconstructed from patient CT data. Young's modulus and the Poisson ratio for each tissue will be adjusted to fit the experience of participating surgeons. PMID:21335882

  19. Effects of RAS on the genesis of embryonal rhabdomyosarcoma

    PubMed Central

    Langenau, David M.; Keefe, Matthew D.; Storer, Narie Y.; Guyon, Jeffrey R.; Kutok, Jeffery L.; Le, Xiuning; Goessling, Wolfram; Neuberg, Donna S.; Kunkel, Louis M.; Zon, Leonard I.

    2007-01-01

    Embryonal rhabdomyosarcoma (ERMS) is a devastating cancer with specific features of muscle differentiation that can result from mutational activation of RAS family members. However, to date, RAS pathway activation has not been reported in a majority of ERMS patients. Here, we have created a zebrafish model of RAS-induced ERMS, in which animals develop externally visible tumors by 10 d of life. Microarray analysis and cross-species comparisons identified two conserved gene signatures found in both zebrafish and human ERMS, one associated with tumor-specific and tissue-restricted gene expression in rhabdomyosarcoma and a second comprising a novel RAS-induced gene signature. Remarkably, our analysis uncovered that RAS pathway activation is exceedingly common in human RMS. We also created a new transgenic coinjection methodology to fluorescently label distinct subpopulations of tumor cells based on muscle differentiation status. In conjunction with fluorescent activated cell sorting, cell transplantation, and limiting dilution analysis, we were able to identify the cancer stem cell in zebrafish ERMS. When coupled with gene expression studies of this cell population, we propose that the zebrafish RMS cancer stem cell shares similar self-renewal programs as those found in activated satellite cells. PMID:17510286

  20. Oncogenic Ras influences the expression of multiple lncRNAs.

    PubMed

    Kotake, Yojiro; Naemura, Madoka; Kitagawa, Kyoko; Niida, Hiroyuki; Tsunoda, Toshiyuki; Shirasawa, Senji; Kitagawa, Masatoshi

    2016-08-01

    Recent ultrahigh-density tiling array and large-scale transcriptome analysis have revealed that large numbers of long non-coding RNAs (lncRNAs) are transcribed in mammals. Several lncRNAs have been implicated in transcriptional regulation, organization of nuclear structure, and post-transcriptional processing. However, the regulation of expression of lncRNAs is less well understood. Here, we show that the exogenous and endogenous expression of an oncogenic form of small GTPase Ras (called oncogenic Ras) decrease the expression of lncRNA ANRIL (antisense non-coding RNA in the INK4 locus), which is involved in the regulation of cellular senescence. We also show that forced expression of oncogenic Ras increases the expression of lncRNA PANDA (p21 associated ncRNA DNA damage activated), which is involved in the regulation of apoptosis. Microarray analysis demonstrated that expression of multiple lncRNAs fluctuated by forced expression of oncogenic Ras. These findings indicate that oncogenic Ras regulates the expression of a large number of lncRNAs including functional lncRNAs, such as ANRIL and PANDA. PMID:25501747

  1. Pleiotrophin mediates hematopoietic regeneration via activation of RAS.

    PubMed

    Himburg, Heather A; Yan, Xiao; Doan, Phuong L; Quarmyne, Mamle; Micewicz, Eva; McBride, William; Chao, Nelson J; Slamon, Dennis J; Chute, John P

    2014-11-01

    Hematopoietic stem cells (HSCs) are highly susceptible to ionizing radiation-mediated death via induction of ROS, DNA double-strand breaks, and apoptotic pathways. The development of therapeutics capable of mitigating ionizing radiation-induced hematopoietic toxicity could benefit both victims of acute radiation sickness and patients undergoing hematopoietic cell transplantation. Unfortunately, therapies capable of accelerating hematopoietic reconstitution following lethal radiation exposure have remained elusive. Here, we found that systemic administration of pleiotrophin (PTN), a protein that is secreted by BM-derived endothelial cells, substantially increased the survival of mice following radiation exposure and after myeloablative BM transplantation. In both models, PTN increased survival by accelerating the recovery of BM hematopoietic stem and progenitor cells in vivo. PTN treatment promoted HSC regeneration via activation of the RAS pathway in mice that expressed protein tyrosine phosphatase receptor-zeta (PTPRZ), whereas PTN treatment did not induce RAS signaling in PTPRZ-deficient mice, suggesting that PTN-mediated activation of RAS was dependent upon signaling through PTPRZ. PTN strongly inhibited HSC cycling following irradiation, whereas RAS inhibition abrogated PTN-mediated induction of HSC quiescence, blocked PTN-mediated recovery of hematopoietic stem and progenitor cells, and abolished PTN-mediated survival of irradiated mice. These studies demonstrate the therapeutic potential of PTN to improve survival after myeloablation and suggest that PTN-mediated hematopoietic regeneration occurs in a RAS-dependent manner. PMID:25250571

  2. Ras regulation of DNA-methylation and cancer

    SciTech Connect

    Patra, Samir Kumar

    2008-04-01

    Genome wide hypomethylation and regional hypermethylation of cancer cells and tissues remain a paradox, though it has received a convincing confirmation that epigenetic switching systems, including DNA-methylation represent a fundamental regulatory mechanism that has an impact on genome maintenance and gene transcription. Methylated cytosine residues of vertebrate DNA are transmitted by clonal inheritance through the strong preference of DNA methyltransferase, DNMT1, for hemimethylated-DNA. Maintenance of methylation patterns is necessary for normal development of mice, and aberrant methylation patterns are associated with many human tumours. DNMT1 interacts with many proteins during cell cycle progression, including PCNA, p53, EZH2 and HP1. Ras family of GTPases promotes cell proliferation by its oncogenic nature, which transmits signals by multiple pathways in both lipid raft dependent and independent fashion. DNA-methylation-mediated repression of DNA-repair protein O6-methylguanine DNA methyltransferase (MGMT) gene and increased rate of K-Ras mutation at codon for amino acids 12 and 13 have been correlated with a secondary role for Ras-effector homologues (RASSFs) in tumourigenesis. Lines of evidence suggest that DNA-methylation associated repression of tumour suppressors and apoptotic genes and ceaseless proliferation of tumour cells are regulated in part by Ras-signaling. Control of Ras GTPase signaling might reduce the aberrant methylation and accordingly may reduce the risk of cancer development.

  3. Oncogenic Ras/Src cooperativity in pancreatic neoplasia

    PubMed Central

    Shields, DJ; Murphy, EA; Desgrosellier, JS; Mielgo, A; Lau, SKM; Barnes, LA; Lesperance, J; Huang, M; Schmedt, C; Tarin, D; Lowy, AM; Cheresh, DA

    2011-01-01

    Pancreas cancer is one of the most lethal malignancies and is characterized by activating mutations of Kras, present in 95% of patients. More than 60% of pancreatic cancers also display increased c-Src activity, which is associated with poor prognosis. Although loss of tumor suppressor function (for example, p16, p53, Smad4) combined with oncogenic Kras signaling has been shown to accelerate pancreatic duct carcinogenesis, it is unclear whether elevated Src activity contributes to Kras-dependent tumorigenesis or is simply a biomarker of disease progression. Here, we demonstrate that in the context of oncogenic Kras, activation of c-Src through deletion of C-terminal Src kinase (CSK) results in the development of invasive pancreatic ductal adenocarcinoma (PDA) by 5–8 weeks. In contrast, deletion of CSK alone fails to induce neoplasia, while oncogenic Kras expression yields PDA at low frequency after a latency of 12 months. Analysis of cell lines derived from Ras/Src-induced PDA’s indicates that oncogenic Ras/Src cooperativity may lead to genomic instability, yet Ras/Src-driven tumor cells remain dependent on Src signaling and as such, Src inhibition suppresses growth of Ras/Src-driven tumors. These findings demonstrate that oncogenic Ras/Src cooperate to accelerate PDA onset and support further studies of Src-directed therapies in pancreatic cancer. PMID:21242978

  4. Ras transformation uncouples the kinesin-coordinated cellular nutrient response.

    PubMed

    Zaganjor, Elma; Weil, Lauren M; Gonzales, Joshua X; Minna, John D; Cobb, Melanie H

    2014-07-22

    The kinesin family members (KIFs) KIF2A and KIF2C depolymerize microtubules, unlike the majority of other kinesins, which transport cargo along microtubules. KIF2A regulates the localization of lysosomes in the cytoplasm, which assists in activation of the mechanistic target of rapamycin complex 1 (mTORC1) on the lysosomal surface. We find that the closely related kinesin KIF2C also influences lysosomal organization in immortalized human bronchial epithelial cells (HBECs). Expression of KIF2C and, to a lesser extent, KIF2A in untransformed and mutant K-Ras-transformed cells is regulated by ERK1/2. Prolonged inhibition of ERK1/2 activation with PD0325901 mimics nutrient deprivation by disrupting lysosome organization and decreasing mTORC1 activity in HBEC, suggesting a long-term mechanism for optimization of mTORC1 activity by ERK1/2. We tested the hypothesis that up-regulation of KIF2C and KIF2A by ERK1/2 caused aberrant lysosomal positioning and mTORC1 activity in a mutant K-Ras-dependent cancer and cancer model. In Ras-transformed cells, however, mTORC1 activity and lysosome organization appear independent of ERK1/2 and these kinesins although ERK1/2 activity and the kinesins are required for Ras-dependent proliferation and migration. We conclude that mutant K-Ras repurposes these signaling and regulatory proteins to support the transformed phenotype. PMID:25002494

  5. Inhibition of ras oncogene: a novel approach to antineoplastic therapy.

    PubMed

    Scharovsky, O G; Rozados, V R; Gervasoni, S I; Matar, P

    2000-01-01

    The most frequently detected oncogene alterations, both in animal and human cancers, are the mutations in the ras oncogene family. These oncogenes are mutated or overexpressed in many human tumors, with a high incidence in tumors of the pancreas, thyroid, colon, lung and certain types of leukemia. Ras is a small guanine nucleotide binding protein that transduces biological information from the cell surface to cytoplasmic components within cells. The signal is transduced to the cell nucleus through second messengers, and it ultimately induces cell division. Oncogenic forms of p21(ras) lead to unregulated, sustained signaling through downstream effectors. The ras family of oncogenes is involved in the development of both primary tumors and metastases making it a good therapeutic target. Several therapeutic approaches to cancer have been developed pointing to reducing the altered gene product or to eliminating its biological function: (1) gene therapy with ribozymes, which are able to break down specific RNA sequences, or with antisense oligonucleotides, (2) immunotherapy through passive or active immunization protocols, and (3) inhibition of p21(ras) farnesylation either by inhibition of farnesyl transferase or synthesis inhibition of farnesyl moieties. PMID:10895051

  6. Clinical simulation as a boundary object in design of health IT-systems.

    PubMed

    Rasmussen, Stine Loft; Jensen, Sanne; Lyng, Karen Marie

    2013-01-01

    Healthcare organizations are very complex, holding numerous stakeholders with various approaches and goals towards the design of health IT-systems. Some of these differences may be approached by applying the concept of boundary objects in a participatory IT-design process. Traditionally clinical simulation provides the opportunity to evaluate the design and the usage of clinical IT-systems without endangering the patients and interrupting clinical work. In this paper we present how clinical simulation additionally holds the potential to function as a boundary object in the design process. The case points out that clinical simulation provides an opportunity for discussions and mutual learning among the various stakeholders involved in design of standardized electronic clinical documentation templates. The paper presents and discusses the use of clinical simulation in the translation, transfer and transformation of knowledge between various stakeholders in a large healthcare organization. PMID:23941951

  7. Hermes CX-7: Air transport system design simulation

    NASA Technical Reports Server (NTRS)

    Amer, Brian; Barter, John; Colucci, Jay; Foley, Caryn; Kockler, James; Rapp, David; Zeiger, Matthew

    1992-01-01

    The Hermes CX-7 has been designed to service the overnight parcel package delivery needs of the cities of Aeroworld as determined in the G-Dome Enterprises market survey. The design optimization centers on the prime goal of servicing the needs of these cities as efficiently and profitably as possible. The greatest factors which affect the design of an aircraft for the mission outlined in the Request for Proposal are cost, construction feasibility and effectiveness of the design. Other influencing factors are given by the constraints of the market, including a maximum takeoff and landing distance of 60 feet, storage capability in a container of size 5 ft. x 3 ft. x 2 ft., cargo packages of 2 inch and 4 inch cubes, and ability to turn with a radius no larger than 60 feet. Safety considerations such as flying at or below Mach one (30 ft/s) and controllability and maintainability of the aircraft must also be designed into the aircraft. Another influential factor is the efficiency of the aircraft which involves optimizations and tradeoffs of such factors as weight, lifting surface sizing, structural redundancy, and material costs.

  8. Identification of a farnesol analog as a Ras function inhibitor using both an in vivo Ras activation sensor and a phenotypic screening approach

    PubMed Central

    Srinivasan, Kamalakkannan; Subramanian, Thangaiah; Spielmann, H. Peter

    2013-01-01

    Mutations in Ras isoforms such as K-Ras, N-Ras, and H-Ras contribute to roughly 85, 15, and 1 % of human cancers, respectively. Proper membrane targeting of these Ras isoforms, a prerequisite for Ras activity, requires farnesylation or geranylgeranylation at the C-terminal CAAX box. We devised an in vivo screening strategy based on monitoring Ras activation and phenotypic physiological outputs for assaying synthetic Ras function inhibitors (RFI). Ras activity was visualized by the trans-location of RBDRaf1-GFP to activated Ras at the plasma membrane. By using this strategy, we screened one synthetic farnesyl substrate analog (AGOH) along with nine putative inhibitors and found that only m-CN-AGOH inhibited Ras activation. Phenotypic analysis of starving cells could be used to monitor polarization, motility, and the inability of these treated cells to aggregate properly during fruiting body formation. Incorporation of AGOH and m-CN-AGOH to cellular proteins was detected by western blot. These screening assays can be incorporated into a high throughput screening format using Dictyostelium discoideum and automated microscopy to determine effective RFIs. These RFI candidates can then be further tested in mammalian systems. PMID:24194124

  9. Architectural design and simulation of a virtual memory

    NASA Technical Reports Server (NTRS)

    Kwok, G.; Chu, Y.

    1971-01-01

    Virtual memory is an imaginary main memory with a very large capacity which the programmer has at his disposal. It greatly contributes to the solution of the dynamic storage allocation problem. The architectural design of a virtual memory is presented which implements by hardware the idea of queuing and scheduling the page requests to a paging drum in such a way that the access of the paging drum is increased many times. With the design, an increase of up to 16 times in page transfer rate is achievable when the virtual memory is heavily loaded. This in turn makes feasible a great increase in the system throughput.

  10. Advanced Simulation Technology to Design Etching Process on CMOS Devices

    NASA Astrophysics Data System (ADS)

    Kuboi, Nobuyuki

    2015-09-01

    Prediction and control of plasma-induced damage is needed to mass-produce high performance CMOS devices. In particular, side-wall (SW) etching with low damage is a key process for the next generation of MOSFETs and FinFETs. To predict and control the damage, we have developed a SiN etching simulation technique for CHxFy/Ar/O2 plasma processes using a three-dimensional (3D) voxel model. This model includes new concepts for the gas transportation in the pattern, detailed surface reactions on the SiN reactive layer divided into several thin slabs and C-F polymer layer dependent on the H/N ratio, and use of ``smart voxels''. We successfully predicted the etching properties such as the etch rate, polymer layer thickness, and selectivity for Si, SiO2, and SiN films along with process variations and demonstrated the 3D damage distribution time-dependently during SW etching on MOSFETs and FinFETs. We confirmed that a large amount of Si damage was caused in the source/drain region with the passage of time in spite of the existing SiO2 layer of 15 nm in the over etch step and the Si fin having been directly damaged by a large amount of high energy H during the removal step of the parasitic fin spacer leading to Si fin damage to a depth of 14 to 18 nm. By analyzing the results of these simulations and our previous simulations, we found that it is important to carefully control the dose of high energy H, incident energy of H, polymer layer thickness, and over-etch time considering the effects of the pattern structure, chamber-wall condition, and wafer open area ratio. In collaboration with Masanaga Fukasawa and Tetsuya Tatsumi, Sony Corporation. We thank Mr. T. Shigetoshi and Mr. T. Kinoshita of Sony Corporation for their assistance with the experiments.

  11. Unfixing Design Fixation: From Cause to Computer Simulation

    ERIC Educational Resources Information Center

    Dong, Andy; Sarkar, Somwrita

    2011-01-01

    This paper argues that design fixation, in part, entails fixation at the level of meta-representation, the representation of the relation between a representation and its reference. In this paper, we present a mathematical model that mimics the idea of how fixation can occur at the meta-representation level. In this model, new abstract concepts…

  12. Simulation and simplified design studies of photovoltaic systems

    SciTech Connect

    Evans, D.L.; Facinelli, W.A.; Koehler, L.P.

    1980-09-01

    Results of TRNSYS simulations of photovoltaic systems with electrical storage are described. Studies of the sensitivity of system performance, in terms of the fraction of the electrical load supplied by the solar energy system, to variables such as array size, battery size, location, time of year, and load shape are reported. An accurate simplified method for predicting array output of max-power photovoltaic systems is presented. A second simplified method, which estimates the overall performance of max-power systems, is developed. Finally, a preliminary technique for predicting clamped-voltage system performance is discussed.

  13. Simulation and simplified design of photovoltaic power systems

    NASA Astrophysics Data System (ADS)

    Evans, D. L.; Facinelli, W. A.; Koehler, L. P.

    Results of TRNSYS simulations of photovoltaic systems with and without battery storage are described. The systems have south facing, flat arrays that are max-power tracked and have one day or less of storage. Studies of the sensitivity of system performance, in terms of the fraction of the electrical load supplied by the solar energy system, to variables such as array size, battery size, location, time of year, and load shape are reported. A simplified method for calculating system performance is described and examples of its accuracy are presented.

  14. First step of glycosylphosphatidylinositol (GPI) biosynthesis cross-talks with ergosterol biosynthesis and Ras signaling in Candida albicans.

    PubMed

    Yadav, Bhawna; Bhatnagar, Shilpi; Ahmad, Mohammad Faiz; Jain, Priyanka; Pratyusha, Vavilala A; Kumar, Pravin; Komath, Sneha Sudha

    2014-02-01

    Candida albicans is a leading cause of fungal infections worldwide. It has several glycosylphosphatidylinositol (GPI)-anchored virulence factors. Inhibiting GPI biosynthesis attenuates its virulence. Building on our previous work, we explore the interaction of GPI biosynthesis in C. albicans with ergosterol biosynthesis and hyphal morphogenesis. This study is also the first report of transcriptional co-regulation existing between two subunits of the multisubunit enzyme complex, GPI-N-acetylglucosaminyltransferase (GPI-GnT), involved in the first step of GPI anchor biosynthesis in eukaryotes. Using mutational analysis, we show that the accessory subunits, GPI2 and GPI19, of GPI-GnT exhibit opposite effects on ergosterol biosynthesis and Ras signaling (which determines hyphal morphogenesis). This is because the two subunits negatively regulate one another; GPI19 mutants show up-regulation of GPI2, whereas GPI2 mutants show up-regulation of GPI19. Two different models were examined as follows. First, the two GPI-GnT subunits independently interact with ergosterol biosynthesis and Ras signaling. Second, the two subunits mutually regulate one another and thereby regulate sterol levels and Ras signaling. Analysis of double mutants of these subunits indicates that GPI19 controls ergosterol biosynthesis through ERG11 levels, whereas GPI2 determines the filamentation by cross-talk with Ras1 signaling. Taken together, this suggests that the first step of GPI biosynthesis talks to and regulates two very important pathways in C. albicans. This could have implications for designing new antifungal strategies. PMID:24356967

  15. Bisphenol A binds to Ras proteins and competes with guanine nucleotide exchange: implications for GTPase-selective antagonists.

    PubMed

    Schöpel, Miriam; Jockers, Katharina F G; Düppe, Peter M; Autzen, Jasmin; Potheraveedu, Veena N; Ince, Semra; Yip, King Tuo; Heumann, Rolf; Herrmann, Christian; Scherkenbeck, Jürgen; Stoll, Raphael

    2013-12-12

    We show for the first time that bisphenol A (10) has the capacity to interact directly with K-Ras and that Rheb weakly binds to bisphenol A (10) and 4,4'-biphenol derivatives. We have characterized these interactions at atomic resolution suggesting that these compounds sterically interfere with the Sos-mediated nucleotide exchange in H- and K-Ras. We show that 4,4'-biphenol (5) selectively inhibits Rheb signaling and induces cell death suggesting that this compound might be a novel candidate for treatment of tuberous sclerosis-mediated tumor growth. Our results propose a new mode of action for bisphenol A (10) that advocates a reduced exposure to this compound in our environment. Our data may lay the foundation for the future design of GTPase-selective antagonists with higher affinity to benefit of the treatment of cancer because K-Ras inhibition is regarded to be a promising strategy with a potential therapeutic window for targeting Sos in Ras-driven tumors. PMID:24266771

  16. Long-term follow-up of patients with resected pancreatic cancer following vaccination against mutant K-ras.

    PubMed

    Wedén, Synne; Klemp, Marianne; Gladhaug, Ivar P; Møller, Mona; Eriksen, Jon Amund; Gaudernack, Gustav; Buanes, Trond

    2011-03-01

    K-ras mutations are frequently found in adenocarcinomas of the pancreas and can elicit mutation-specific immune responses. Targeting the immune system against mutant Ras may thus influence the clinical course of the disease. Twenty-three patients who were vaccinated after surgical resection for pancreatic adenocarcinoma (22 pancreaticoduodenectomies, one distal resection), in two previous Phase I/II clinical trials, were followed for more than 10 years with respect to long-term immunological T-cell reactivity and survival. The vaccine was composed of long synthetic mutant ras peptides designed mainly to elicit T-helper responses. Seventeen of 20 evaluable patients (85%) responded immunologically to the vaccine. Median survival for all patients was 27.5 months and 28 months for immune responders. The 5-year survival was 22% and 29%, respectively. Strikingly, 10-year survival was 20% (four patients out of 20 evaluable) versus zero (0/87) in a cohort of nonvaccinated patient treated in the same period. Three patients mounted a memory response up to 9 years after vaccination. The present observation of long-term immune response together with 10-year survival following surgical resection indicates that K-ras vaccination may consolidate the effect of surgery and represent an adjuvant treatment option for the future. PMID:20473937

  17. The Differential Effects of Wild-Type and Mutated K-Ras on MST2 Signaling Are Determined by K-Ras Activation Kinetics

    PubMed Central

    Romano, David; Maccario, Helene; Doherty, Carolanne; Quinn, Niall P.

    2013-01-01

    K-Ras is frequently mutated in human cancers. Mutant (mt) K-Ras can stimulate both oncogenic transformation and apoptosis through activation of extracellular signal-regulated kinase (ERK) and AKT pathways and the MST2 pathway, respectively. The biological outcome is determined by the balance and cross talk between these pathways. In colorectal cancer (CRC), a K-Ras mutation is negatively correlated with MST2 expression, as mt K-Ras can induce apoptosis by activating the MST2 pathway. However, wild-type (wt) K-Ras can prevent the activation of the MST2 pathway upon growth factor stimulation and enable transformation by mt K-Ras in CRC cells that express MST2. Here we have investigated the mechanism by which wt and mt K-Ras differentially regulate the MST2 pathway and MST2-dependent apoptosis. The ability of K-Ras to activate MST2 and MST2-dependent apoptosis is determined by the differential activation kinetics of mt K-Ras and wt K-Ras. Chronic activation of K-Ras by mutation or overexpression of Ras exchange factors results in the activation of MST2 and LATS1, increased MST2-LATS1 complex formation, and apoptosis. In contrast, transient K-Ras activation upon epidermal growth factor (EGF) stimulation prevents the formation of the MST2-LATS1 complex in an AKT-dependent manner. Our data suggest that the close relationship between Ras prosurvival and proapoptotic signaling is coordinated via the differential regulation of the MST2-LATS1 interaction by transient and chronic stimuli. PMID:23459937

  18. Use of piloted simulation for high-angle-of-attack agility research and design criteria development

    NASA Technical Reports Server (NTRS)

    Ogburn, Marilyn E.; Foster, John V.; Hoffler, Keith D.

    1991-01-01

    The application of piloted simulations in the development of advanced fighter aircraft is reviewed in the context of the NASA High-Angle-of-Attack Technology Program (HATP). The HATP combines wind-tunnel experiments, computational aerodynamics, piloted simulations, and flight tests on a modified F-18 testbed aircraft and utilizes the experience and facilities of several NASA centers. Consideration is given to the role of simulation in the overall research process, simulation capabilities and software requirements, simulation flexibility and fidelity, evaluation maneuvers, the role of simulator pilots in evaluations, the analysis of simulation results, flight validation of maneuvers and rating approaches, and the use of simulations to define design criteria. Extensive diagrams, graphs, and flow charts are included.

  19. Design and validation of inert homemade explosive simulants for X-ray-based inspection systems

    NASA Astrophysics Data System (ADS)

    Faust, Anthony A.; Nacson, Sabatino; Koffler, Bruce; Bourbeau, Éric; Gagne, Louis; Laing, Robin; Anderson, C. J.

    2014-05-01

    Transport Canada (TC), the Canadian Armed Forces, and other public security agencies have an interest in the assessment of the potential utility of advanced explosives detection technologies to aid in the detection and interdiction of commercial grade, military grade, and homemade or improvised explosives (HME or IE). The availability of suitable, non-hazardous, non-toxic, explosive simulants is of concern when assessing the potential utility of such detection systems. Lack of simulants limits the training opportunities, and ultimately the detection probability, of security personnel using these systems. While simulants for commercial and military grade explosives are available for a wide variety of detection technologies, the design and production of materials to simulate improvised explosives has not kept pace with this emerging threat. Funded by TC and the Canadian Safety and Security Program, Defence Research and Development Canada (DRDC), Visiontec Systems, and Optosecurity engaged in an effort to develop inert, non-toxic Xray interrogation simulants for IE materials such as ammonium nitrate, potassium chlorate, and triacetone triperoxide. These simulants were designed to mimic key X-ray interrogation-relevant material properties of real improvised explosives, principally their bulk density and effective atomic number. Different forms of the simulants were produced and tested, simulating the different explosive threat formulations that could be encountered by front line security workers. These simulants comply with safety and stability requirements, and as best as possible match form and homogeneity. This paper outlines the research program, simulant design, and validation.

  20. Unified Simulation and Analysis Framework for Deep Space Navigation Design

    NASA Technical Reports Server (NTRS)

    Anzalone, Evan; Chuang, Jason; Olsen, Carrie

    2013-01-01

    As the technology that enables advanced deep space autonomous navigation continues to develop and the requirements for such capability continues to grow, there is a clear need for a modular expandable simulation framework. This tool's purpose is to address multiple measurement and information sources in order to capture system capability. This is needed to analyze the capability of competing navigation systems as well as to develop system requirements, in order to determine its effect on the sizing of the integrated vehicle. The development for such a framework is built upon Model-Based Systems Engineering techniques to capture the architecture of the navigation system and possible state measurements and observations to feed into the simulation implementation structure. These models also allow a common environment for the capture of an increasingly complex operational architecture, involving multiple spacecraft, ground stations, and communication networks. In order to address these architectural developments, a framework of agent-based modules is implemented to capture the independent operations of individual spacecraft as well as the network interactions amongst spacecraft. This paper describes the development of this framework, and the modeling processes used to capture a deep space navigation system. Additionally, a sample implementation describing a concept of network-based navigation utilizing digitally transmitted data packets is described in detail. This developed package shows the capability of the modeling framework, including its modularity, analysis capabilities, and its unification back to the overall system requirements and definition.

  1. SKA Weak Lensing II: Simulated Performance and Survey Design Considerations

    NASA Astrophysics Data System (ADS)

    Bonaldi, Anna; Harrison, Ian; Camera, Stefano; Brown, Michael L.

    2016-08-01

    We construct a pipeline for simulating weak lensing cosmology surveys with the Square Kilometre Array (SKA), taking as inputs telescope sensitivity curves; correlated source flux, size and redshift distributions; a simple ionospheric model; source redshift and ellipticity measurement errors. We then use this simulation pipeline to optimise a 2-year weak lensing survey performed with the first deployment of the SKA (SKA1). Our assessments are based on the total signal-to-noise of the recovered shear power spectra, a metric that we find to correlate very well with a standard dark energy figure of merit. We first consider the choice of frequency band, trading off increases in number counts at lower frequencies against poorer resolution; our analysis strongly prefers the higher frequency Band 2 (950-1760 MHz) channel of the SKA-MID telescope to the lower frequency Band 1 (350-1050 MHz). Best results would be obtained by allowing the centre of Band 2 to shift towards lower frequency, around 1.1 GHz. We then move on to consider survey size, finding that an area of 5,000 square degrees is optimal for most SKA1 instrumental configurations. Finally, we forecast the performance of a weak lensing survey with the second deployment of the SKA. The increased survey size (3π steradian) and sensitivity improves both the signal-to-noise and the dark energy metrics by two orders of magnitude.

  2. Designing and implementing nervous system simulations on LEGO robots.

    PubMed

    Blustein, Daniel; Rosenthal, Nikolai; Ayers, Joseph

    2013-01-01

    We present a method to use the commercially available LEGO Mindstorms NXT robotics platform to test systems level neuroscience hypotheses. The first step of the method is to develop a nervous system simulation of specific reflexive behaviors of an appropriate model organism; here we use the American Lobster. Exteroceptive reflexes mediated by decussating (crossing) neural connections can explain an animal's taxis towards or away from a stimulus as described by Braitenberg and are particularly well suited for investigation using the NXT platform.(1) The nervous system simulation is programmed using LabVIEW software on the LEGO Mindstorms platform. Once the nervous system is tuned properly, behavioral experiments are run on the robot and on the animal under identical environmental conditions. By controlling the sensory milieu experienced by the specimens, differences in behavioral outputs can be observed. These differences may point to specific deficiencies in the nervous system model and serve to inform the iteration of the model for the particular behavior under study. This method allows for the experimental manipulation of electronic nervous systems and serves as a way to explore neuroscience hypotheses specifically regarding the neurophysiological basis of simple innate reflexive behaviors. The LEGO Mindstorms NXT kit provides an affordable and efficient platform on which to test preliminary biomimetic robot control schemes. The approach is also well suited for the high school classroom to serve as the foundation for a hands-on inquiry-based biorobotics curriculum. PMID:23728477

  3. LiteVis: Integrated Visualization for Simulation-Based Decision Support in Lighting Design.

    PubMed

    Sorger, Johannes; Ortner, Thomas; Luksch, Christian; Schwärzler, Michael; Gröller, Eduard; Piringer, Harald

    2016-01-01

    State-of-the-art lighting design is based on physically accurate lighting simulations of scenes such as offices. The simulation results support lighting designers in the creation of lighting configurations, which must meet contradicting customer objectives regarding quality and price while conforming to industry standards. However, current tools for lighting design impede rapid feedback cycles. On the one side, they decouple analysis and simulation specification. On the other side, they lack capabilities for a detailed comparison of multiple configurations. The primary contribution of this paper is a design study of LiteVis, a system for efficient decision support in lighting design. LiteVis tightly integrates global illumination-based lighting simulation, a spatial representation of the scene, and non-spatial visualizations of parameters and result indicators. This enables an efficient iterative cycle of simulation parametrization and analysis. Specifically, a novel visualization supports decision making by ranking simulated lighting configurations with regard to a weight-based prioritization of objectives that considers both spatial and non-spatial characteristics. In the spatial domain, novel concepts support a detailed comparison of illumination scenarios. We demonstrate LiteVis using a real-world use case and report qualitative feedback of lighting designers. This feedback indicates that LiteVis successfully supports lighting designers to achieve key tasks more efficiently and with greater certainty. PMID:26529708

  4. K-Ras4B proteins are expressed in the nucleolus: Interaction with nucleolin.

    PubMed

    Birchenall-Roberts, Maria C; Fu, Tao; Kim, Soo-Gyung; Huang, Ying K; Dambach, Michael; Resau, James H; Ruscetti, Francis W

    2006-09-22

    Kirsten Ras4B (K-Ras4B) is a potent onco-protein that is expressed in the majority of human cell types and is frequently mutated in carcinomas. K-Ras4B, like other members of the Ras family of proteins, is considered to be a cytoplasmic protein that must be localized to the plasma membrane for activation. Here, using confocal microscopy and biochemical analysis, we show that K-Ras4B, but not H-Ras or the closely related K-Ras4A, is also present in the nucleoli of normal and transformed cells. Subcellular fractionation and immunostaining show that K-Ras4B is located not only in the cytoplasm, but also in the nucleolar compartment. Modification of a C-terminal hexa-lysine motif unique to K-Ras4B results in exclusively cytoplasmic forms of the protein. Nucleolin, a pleiotropic regulator of cellular processes, including transcriptional regulation, is also characterized by a nucleolar-like nuclear appearance. We show that K-Ras4B and nucleolin co-localize within the nucleus and that nucleolin physically associates with K-Ras4B. Inhibition of K-Ras4B/nucleolin association blocked nucleolar localization of K-Ras4B. Using siRNA to knockdown the expression of nucleolin eliminated the nucleolar localization of K-Ras4B and significantly repressed the activation of the well-characterized K-Ras4B transcriptional target Ap-1, but stimulated Elk1. These data provide evidence of a nucleolar localization of K-Ras4B and describe a functional association between K-Ras4B and nucleolin. PMID:16889753

  5. K-Ras4B proteins are expressed in the nucleolus: Interaction with nucleolin

    SciTech Connect

    Birchenall-Roberts, Maria C. . E-mail: birchena@mail.ncifcrf.gov; Fu, Tao; Kim, Soo-Gyung; Huang, Ying K.; Dambach, Michael; Resau, James H.; Ruscetti, Francis W.

    2006-09-22

    Kirsten Ras4B (K-Ras4B) is a potent onco-protein that is expressed in the majority of human cell types and is frequently mutated in carcinomas. K-Ras4B, like other members of the Ras family of proteins, is considered to be a cytoplasmic protein that must be localized to the plasma membrane for activation. Here, using confocal microscopy and biochemical analysis, we show that K-Ras4B, but not H-Ras or the closely related K-Ras4A, is also present in the nucleoli of normal and transformed cells. Subcellular fractionation and immunostaining show that K-Ras4B is located not only in the cytoplasm, but also in the nucleolar compartment. Modification of a C-terminal hexa-lysine motif unique to K-Ras4B results in exclusively cytoplasmic forms of the protein. Nucleolin, a pleiotropic regulator of cellular processes, including transcriptional regulation, is also characterized by a nucleolar-like nuclear appearance. We show that K-Ras4B and nucleolin co-localize within the nucleus and that nucleolin physically associates with K-Ras4B. Inhibition of K-Ras4B/nucleolin association blocked nucleolar localization of K-Ras4B. Using siRNA to knockdown the expression of nucleolin eliminated the nucleolar localization of K-Ras4B and significantly repressed the activation of the well-characterized K-Ras4B transcriptional target Ap-1, but stimulated Elk1. These data provide evidence of a nucleolar localization of K-Ras4B and describe a functional association between K-Ras4B and nucleolin.

  6. Galectin-1 dimers can scaffold Raf-effectors to increase H-ras nanoclustering.

    PubMed

    Blaževitš, Olga; Mideksa, Yonatan G; Šolman, Maja; Ligabue, Alessio; Ariotti, Nicholas; Nakhaeizadeh, Hossein; Fansa, Eyad K; Papageorgiou, Anastassios C; Wittinghofer, Alfred; Ahmadian, Mohammad R; Abankwa, Daniel

    2016-01-01

    Galectin-1 (Gal-1) dimers crosslink carbohydrates on cell surface receptors. Carbohydrate-derived inhibitors have been developed for cancer treatment. Intracellularly, Gal-1 was suggested to interact with the farnesylated C-terminus of Ras thus specifically stabilizing GTP-H-ras nanoscale signalling hubs in the membrane, termed nanoclusters. The latter activity may present an alternative mechanism for how overexpressed Gal-1 stimulates tumourigenesis. Here we revise the current model for the interaction of Gal-1 with H-ras. We show that it indirectly forms a complex with GTP-H-ras via a high-affinity interaction with the Ras binding domain (RBD) of Ras effectors. A computationally generated model of the Gal-1/C-Raf-RBD complex is validated by mutational analysis. Both cellular FRET as well as proximity ligation assay experiments confirm interaction of Gal-1 with Raf proteins in mammalian cells. Consistently, interference with H-rasG12V-effector interactions basically abolishes H-ras nanoclustering. In addition, an intact dimer interface of Gal-1 is required for it to positively regulate H-rasG12V nanoclustering, but negatively K-rasG12V nanoclustering. Our findings suggest stacked dimers of H-ras, Raf and Gal-1 as building blocks of GTP-H-ras-nanocluster at high Gal-1 levels. Based on our results the Gal-1/effector interface represents a potential drug target site in diseases with aberrant Ras signalling. PMID:27087647

  7. Galectin-1 dimers can scaffold Raf-effectors to increase H-ras nanoclustering

    PubMed Central

    Blaževitš, Olga; Mideksa, Yonatan G.; Šolman, Maja; Ligabue, Alessio; Ariotti, Nicholas; Nakhaeizadeh, Hossein; Fansa, Eyad K.; Papageorgiou, Anastassios C.; Wittinghofer, Alfred; Ahmadian, Mohammad R.; Abankwa, Daniel

    2016-01-01

    Galectin-1 (Gal-1) dimers crosslink carbohydrates on cell surface receptors. Carbohydrate-derived inhibitors have been developed for cancer treatment. Intracellularly, Gal-1 was suggested to interact with the farnesylated C-terminus of Ras thus specifically stabilizing GTP-H-ras nanoscale signalling hubs in the membrane, termed nanoclusters. The latter activity may present an alternative mechanism for how overexpressed Gal-1 stimulates tumourigenesis. Here we revise the current model for the interaction of Gal-1 with H-ras. We show that it indirectly forms a complex with GTP-H-ras via a high-affinity interaction with the Ras binding domain (RBD) of Ras effectors. A computationally generated model of the Gal-1/C-Raf-RBD complex is validated by mutational analysis. Both cellular FRET as well as proximity ligation assay experiments confirm interaction of Gal-1 with Raf proteins in mammalian cells. Consistently, interference with H-rasG12V-effector interactions basically abolishes H-ras nanoclustering. In addition, an intact dimer interface of Gal-1 is required for it to positively regulate H-rasG12V nanoclustering, but negatively K-rasG12V nanoclustering. Our findings suggest stacked dimers of H-ras, Raf and Gal-1 as building blocks of GTP-H-ras-nanocluster at high Gal-1 levels. Based on our results the Gal-1/effector interface represents a potential drug target site in diseases with aberrant Ras signalling. PMID:27087647

  8. Comparison of liver oncogenic potential among human RAS isoforms

    PubMed Central

    Chung, Sook In; Moon, Hyuk; Ju, Hye-Lim; Kim, Dae Yeong; Cho, Kyung Joo; Ribback, Silvia; Dombrowski, Frank; Calvisi, Diego F.; Ro, Simon Weonsang

    2016-01-01

    Mutation in one of three RAS genes (i.e., HRAS, KRAS, and NRAS) leading to constitutive activation of RAS signaling pathways is considered a key oncogenic event in human carcinogenesis. Whether activated RAS isoforms possess different oncogenic potentials remains an unresolved question. Here, we compared oncogenic properties among RAS isoforms using liver-specific transgenesis in mice. Hydrodynamic transfection was performed using transposons expressing short hairpin RNA downregulating p53 and an activated RAS isoform, and livers were harvested at 23 days after gene delivery. No differences were found in the hepatocarcinogenic potential among RAS isoforms, as determined by both gross examination of livers and liver weight per body weight ratio (LW/BW) of mice expressing HRASQ61L, KRAS4BG12V and NRASQ61K. However, the tumorigenic potential differed significantly between KRAS splicing variants. The LW/BW ratio in KRAS4AG12V mice was significantly lower than in KRAS4BG12V mice (p < 0.001), and KRAS4AG12V mice lived significantly longer than KRRAS4BG12V mice (p < 0.0001). Notably, tumors from KRAS4AG12V mice displayed higher expression of the p16INK4A tumor suppressor when compared with KRAS4BG12V tumors. Forced overexpression of p16INK4A significantly reduced tumor growth in KRAS4BG12V mice, suggesting that upregulation of p16INK4A by KRAS4AG12V presumably delays tumor development driven by the latter oncogene. PMID:26799184

  9. Design and Analysis of Missile Systems through CFD Simulations

    NASA Astrophysics Data System (ADS)

    Chakraborty, Debasis

    2010-10-01

    Development of indigenous CFD codes and their applications for complex aerodynamic and propulsive flow problems pertaining to DRDO missiles are presented. Grid generators, 3D Euler and Navier Stokes solvers are developed in-house using state of art numerical techniques and physical models. These softwares are used extensively for aerodynamic characterization of missiles over a wide range of Mach number, angle of attack, control surface deflection and store separation studies. Significant contributions are made in the design of high speed propulsion systems of various ongoing and future missiles through CFD analysis internal flow field. Important design modifications were suggested and the propulsion system performances were optimized. Capabilities have been developed for many advanced topics including computational aeroelasticity, coupled Euler Boltzmann solver, etc.

  10. Design, testing, and simulation of microscale gas chromatography columns

    SciTech Connect

    Hudson, M.L.; Kottenstette, R.; Matzke, C.M.; Frye-Mason, G.C.; Shollenberger, K.A.; Adkins, D.R.; Wong, C.C.

    1998-08-01

    A microscale gas chromatography column is one component in a microscale chemistry laboratory for detecting chemical agents. Several columns were fabricated using the Bosch etch process which allows deep, high aspect ratio channels of rectangular cross-section. A design tool, based on analytical models, was developed to evaluate the effects of operating conditions and column specifications on separation resolution and time. The effects of slip flow, channel configuration, and cross-sectional shape were included to evaluate the differences between conventional round, straight columns and the microscale rectangular, spiral columns. Experimental data were obtained and compared with the predicted flowrates and theoretical number of plates. The design tool was then employed to select more optimum channel dimensions and operating conditions for high resolution separations.

  11. One-dimensional disk model simulation for klystron design

    SciTech Connect

    Yonezawa, H.; Okazaki, Y.

    1984-05-01

    In 1982, one of the authors (Okazaki), of Toshiba Corporation, wrote a one-dimensional, rigid-disk model computer program <1> to serve as a reliable design tool for the 150 MW klystron development project. This is an introductory note for the users of this program. While reviewing the so-called disk programs presently available, hypotheses such as gridded interaction gaps, a linear relation between phase and position, and so on, were found. These hypotheses bring serious limitations and uncertainties into the computational results. JPNDISK was developed to eliminate these defects, to follow the equations of motion as rigorously as possible, and to obtain self-consistent solutions for the gap voltages and the electron motion. Although some inaccuracy may be present in the relativistic region, JPNDISK, in its present form, seems a most suitable tool for klystron design; it is both easy and inexpensive to use.

  12. Rainwater catchment system design using simulated future climate data

    NASA Astrophysics Data System (ADS)

    Wallace, Corey D.; Bailey, Ryan T.; Arabi, Mazdak

    2015-10-01

    Rainwater harvesting techniques are used worldwide to augment potable water supply, provide water for small-scale irrigation practices, increase rainwater-use efficiency for sustained crop growth in arid and semi-arid regions, decrease urban stormwater flow volumes, and in general to relieve dependency on urban water resources cycles. A number of methods have been established in recent years to estimate reliability of rainwater catchment systems (RWCS) and thereby properly size the components (roof catchment area, storage tank size) of the system for a given climatic region. These methods typically use historical or stochastically-generated rainfall patterns to quantify system performance and optimally size the system, with the latter accounting for possible rainfall scenarios based on statistical relationships of historical rainfall patterns. To design RWCS systems that can sustainably meet water demand under future climate conditions, this paper introduces a method that employs climatic data from general circulation models (GCMs) to develop a suite of catchment area vs. storage size design curves that capture uncertainty in future climate scenarios. Monthly rainfall data for the 2010-2050 time period is statistically downscaled to daily values using a Markov chain algorithm, with results used only from GCMs that yield rainfall patterns that are statistically consistent with historical rainfall patterns. The process is demonstrated through application to two climatic regions of the Federated States of Micronesia (FSM) in the western Pacific, wherein the majority of the population relies on rainwater harvesting for potable water supply. Through the use of design curves, communities can provide household RWCS that achieve a certain degree of storage reliability. The method described herein can be applied generally to any geographic region. It can be used to first, assess the future performance of existing household systems; and second, to design or modify systems

  13. Optimal seat suspension design based on minimum "simulated subjective response".

    PubMed

    Wan, Y; Schimmels, J M

    1997-11-01

    This work addresses a method for improving vertical whole body vibration isolation through optimal seat suspension design. The primary thrusts of this investigation are: (1) the development of a simple model that captures the essential dynamics of a seated human exposed to vertical vibration, (2) the selection and evaluation of several standards for assessing human sensitivity to vertical vibration, and (3) the determination of the seat suspension parameters that minimize these standards to yield optimal vibration isolation. Results show that the optimal seat and cushion damping coefficients depend very much on the selection of the vibration sensitivity standard and on the lower bound of the stiffnesses used in the constrained optimization procedure. In all cases, however, the optimal seat damping obtained here is significantly larger (by than a factor of 10) than that obtained using existing seat suspension design methods or from previous optimal suspension studies. This research also indicates that the existing means of assessing vibration in suspension design (ISO 7096) requires modification. PMID:9407279

  14. Design, development and testing of an ambient lighting simulator for external illumination of a transport simulator cockpit

    NASA Technical Reports Server (NTRS)

    Batson, Vernon M.; Gupton, Lawrence E.

    1990-01-01

    Researchers at the NASA-Langley Research Center several years ago began to examine concepts for a facility which could simulate the full range of lighting conditions encountered in flight. The purpose of this facility was to evaluate advanced technology display devices in a cockpit environment. The Aircraft Cockpit Ambient Lighting Simulation System (ACALSS) has been developed to meet that need. The ACALSS surrounds a wide-body part-task simulator cockpit, the Advanced Display Evaluation Cockpit, and interfaces with a VAX 11/780 computer, which is used to host both a math model of a modern transport aircraft and a solar motion model (which animates a servoed sun simulator). Several concepts were evaluated and an efficient design using an ellipsoid reflector and Fresnel luminaires was selected for implementation.

  15. Design and implementation of interactive strap-down inertial navigation simulation system for UAV

    NASA Astrophysics Data System (ADS)

    Cheng, Chuan-qi; Cheng, Xiang; Hao, Xiang-yang; Zhao, Man-dan

    2016-01-01

    Strap-down inertial navigation system (SINS) is widely used in military field, to facilitate the study of SINS algorithms and various coupled navigation algorithms, a simulation system of SINS is designed. Based on modular design, with good portability and expansibility, the system consists of four independent modules: analysis module of motion state, trajectory simulator, IMU simulation module and SINS calculation module. With graphical interface, the system can control every motion state of the trajectory, which is convenient to generate various trajectories efficiently. Using rotation vector attitude algorithm to process simulation data, experiment results show that the attitude, velocity and position error is consistent with the theoretical value, which verifies the rationality of the simulation model and the availability of the simulation system.

  16. Design and simulation of a plant control system for a GCFR demonstration plant

    SciTech Connect

    Estrine, E.A.; Greiner, H.G.

    1980-02-01

    A plant control system is being designed for a 300 MW(e) Gas Cooled Fast Breeder Reactor (GCFR) demonstration plant. Control analysis is being performed as an integral part of the plant design process to ensure that control requirements are satisfied as the plant design evolves. Plant models and simulations are being developed to generate information necessary to further define control system requirements for subsequent plant design iterations.

  17. Design and simulation of satellite attitude control system based on Simulink and VR

    NASA Astrophysics Data System (ADS)

    Zhang, Yang; Gan, Qingbo; Kang, Jingshu

    2016-01-01

    In order to research satellite attitude control system design and visual simulation, the simulation framework of satellite dynamics and attitude control using Simulink were established. The design of satellite earth-oriented control system based on quaternion feedback was completed. The 3D scene based on VR was created and models in the scene were driven by simulation data of Simulink. By coordinate transformation. successful observing the scene in inertial coordinate system, orbit coordinate system and body coordinate system. The result shows that application of simulation method of Simulink combined with VR in the design of satellite attitude control system field, has the advantages of high confidence level, hard real-time property, multi-perspective and multi-coordinate system observing the scene, and improves the comprehensibility and accuracy of the design.

  18. Cost performance satellite design using queueing theory. [via digital simulation

    NASA Technical Reports Server (NTRS)

    Hein, G. F.

    1975-01-01

    A modified Poisson arrival, infinite server queuing model is used to determine the effects of limiting the number of broadcast channels (C) of a direct broadcast satellite used for public service purposes (remote health care, education, etc.). The model is based on the reproductive property of the Poisson distribution. A difference equation has been developed to describe the change in the Poisson parameter. When all initially delayed arrivals reenter the system a (C plus 1) order polynomial must be solved to determine the effective value of the Poisson parameter. When less than 100% of the arrivals reenter the system the effective value must be determined by solving a transcendental equation. The model was used to determine the minimum number of channels required for a disaster warning satellite without degradation in performance. Results predicted by the queuing model were compared with the results of digital simulation.

  19. Simulation studies for design optimisation of a scintillator plate calorimeter

    SciTech Connect

    Proudfoot, J.; Job, P.K.; Trost, H.J. ); Handler, T. ); Gabriel, T. )

    1990-01-01

    Results on simulations studies relating to the optimisation of a sampling scintillator plate calorimeter for an SSC detector system are presented. These studies show that whereas a compensating sampling geometry can be obtained using a variety of configurations using either lead or depleted uranium as the principal absorber, no configuration based on a pure iron absorber is compensating. Unlike in a lead system, delayed energy release from long lived shower products produced in a uranium system pose a serious pile up problem. Therefore we advocate the use of lead as the principal absorber in this calorimeter. Work on optimisation of the mechanical structure is in progress and results are presented on issues such as structural support, tolerances and on the degradation in response due to other detector material within the volume of the calorimeter. 8 refs., 16 figs.

  20. Lunar Regolith Characterization for Simulant Design and Evaluation

    NASA Technical Reports Server (NTRS)

    Schrader, Christian M.; Stoeser, Douglas; Rickman, Douglas; Wentworth, Susan J.; Mclemore, Carole; Fikes, John; McKay, David S.

    2009-01-01

    NASA's Marshall Space Flight Center (MSFC), in conjunction with the United States Geological Survey (USGS), is implementing a new data acquisition strategy to support the development and evaluation of lunar regolith simulants. The objective is to characterize the variance in particle composition, size, shape, and bulk density of the lunar regolith. Apollo drive and drill cores are the preferred samples as they allow for investigation of variation with depth, and many proposed operations on the moon will involve excavation of lunar regolith to depths of at least tens of centimeters. Multiple Apollo cores will be sampled multiple times along their vertical axes and analyzed. This will permit statistical statements about variation both within a core, between closely spaced cores, and between distant areas.

  1. Simulating Water Markets to Help Design Water Rights Regimes

    NASA Astrophysics Data System (ADS)

    Harou, J. J.; Erfani, T.; Huskova, I.; Binions, O.

    2012-12-01

    In many catchments in England no further licenses are available from the Environmental regulator that provides them. The possibility of trading water between license holders has been recognized as a potentially effective and economically efficient strategy to mitigate increasing scarcity. Although trading licenses has been possible since several years, it very rarely happens (roughly 50 trades in 8 years). Several barriers to trade exist including lack of sufficient and prolonged scarcity, license-holder unwillingness to risk future renewal, likelihood license will be downgraded during a trade, duration of time required for approving a trade, etc. Regulators seek to make policy changes so that their inability to grant new licenses will not harm the local and national economy. What policy changes will most cost-effectively increase trading and allow it to effectively reduce the economic cost of scarcity events? A screening tool that could help evaluate problems and advantages of different regulatory solutions, and that could serve to test, assuming transaction costs can be quantified, their effect on trading under specific conditions would be useful. We propose such a water market simulator that predicts economically efficient pair-wise trade (between willing buyers and sellers) and represents the interaction of trades with natural hydrological flows, engineered infrastructure and a particular regulatory regime. The model emulates license-holders' willingness to engage in short-term trade transactions. In their initial form different 'agents' (license holders) are represented using an economic benefit function of water use which is supplemented by rules to represent behavioral or other characteristics of realistic system behavior. A case study based on the river Ouse basin (UK) is made to test the model. The model simulates the catchment weekly over several years considering reservoirs and pair-wise specific transaction costs. Several regulatory policies are tested

  2. The Tumor Suppressor DiRas3 Forms a Complex with H-Ras and C-RAF Proteins and Regulates Localization, Dimerization, and Kinase Activity of C-RAF*

    PubMed Central

    Baljuls, Angela; Beck, Matthias; Oenel, Ayla; Robubi, Armin; Kroschewski, Ruth; Hekman, Mirko; Rudel, Thomas; Rapp, Ulf R.

    2012-01-01

    The maternally imprinted Ras-related tumor suppressor gene DiRas3 is lost or down-regulated in more than 60% of ovarian and breast cancers. The anti-tumorigenic effect of DiRas3 is achieved through several mechanisms, including inhibition of cell proliferation, motility, and invasion, as well as induction of apoptosis and autophagy. Re-expression of DiRas3 in cancer cells interferes with the signaling through Ras/MAPK and PI3K. Despite intensive research, the mode of interference of DiRas3 with the Ras/RAF/MEK/ERK signal transduction is still a matter of speculation. In this study, we show that DiRas3 associates with the H-Ras oncogene and that activation of H-Ras enforces this interaction. Furthermore, while associated with DiRas3, H-Ras is able to bind to its effector protein C-RAF. The resulting multimeric complex consisting of DiRas3, C-RAF, and active H-Ras is more stable than the two protein complexes H-Ras·C-RAF or H-Ras·DiRas3, respectively. The consequence of this complex formation is a DiRas3-mediated recruitment and anchorage of C-RAF to components of the membrane skeleton, suppression of C-RAF/B-RAF heterodimerization, and inhibition of C-RAF kinase activity. PMID:22605333

  3. Design and Application of Interactive Simulations in Problem-Solving in University-Level Physics Education

    ERIC Educational Resources Information Center

    Ceberio, Mikel; Almudí, José Manuel; Franco, Ángel

    2016-01-01

    In recent years, interactive computer simulations have been progressively integrated in the teaching of the sciences and have contributed significant improvements in the teaching-learning process. Practicing problem-solving is a key factor in science and engineering education. The aim of this study was to design simulation-based problem-solving…

  4. Designing a Virtual Olympic Games Framework by Using Simulation in Web 2.0 Technologies

    ERIC Educational Resources Information Center

    Stoilescu, Dorian

    2013-01-01

    Instructional simulation had major difficulties in the past for offering limited possibilities in practice and learning. This article proposes a link between instructional simulation and Web 2.0 technologies. More exactly, I present the design of the Virtual Olympic Games Framework (VOGF), as a significant demonstration of how interactivity in…

  5. Design of an Indoor Sonic Boom Simulator at NASA Langley Research Center

    NASA Technical Reports Server (NTRS)

    Klos, Jacob; Sullivan, Brenda M.; Shepherd, Kevin P.

    2008-01-01

    Construction of a simulator to recreate the soundscape inside residential buildings exposed to sonic booms is scheduled to start during the summer of 2008 at NASA Langley Research Center. The new facility should be complete by the end of the year. The design of the simulator allows independent control of several factors that create the indoor soundscape. Variables that will be isolated include such factors as boom duration, overpressure, rise time, spectral shape, level of rattle, level of squeak, source of rattle and squeak, level of vibration and source of vibration. Test subjects inside the simulator will be asked to judge the simulated soundscape, which will represent realistic indoor boom exposure. Ultimately, this simulator will be used to develop a functional relationship between human response and the sound characteristics creating the indoor soundscape. A conceptual design has been developed by NASA personnel, and is currently being vetted through small-scale risk reduction tests that are being performed in-house. The purpose of this document is to introduce the conceptual design, identify how the indoor response will be simulated, briefly outline some of the risk reduction tests that have been completed to vet the design, and discuss the impact of these tests on the simulator design.

  6. The role of advanced engineering simulation in model-based design

    SciTech Connect

    Hommert, P.J.; Biffle, J.H.

    1995-03-01

    The agile manufacturing paradigm engenders many new concepts and work approaches for manufacturing operations. A technology often invoked in the concept of agility is modeling and simulation. Few would disagree that modeling and simulation holds the potential to substantially reduce the product development cycle and lead to improve product reliability and performance. Advanced engineering simulation can impact manufacturing in three areas: process design, product design, and process control. However, despite that promise, the routine utilization of modeling and simulation by industry within the design process is very limited. Advanced simulation is still used primarily in a troubleshooting mode examining design or process problems after the fact. Sandia National Laboratories has been engaged in the development of advanced engineering simulation tools for many years and more recently has begun to focus on the application of such models to manufacturing processes important for the defense industry. These efforts involve considerable interaction and cooperative research with US industry. Based upon this experience, this presentation examines the elements that are necessary for advanced engineering simulation to become an integral part of the design process.

  7. Analyzing and designing object-oriented missile simulations with concurrency

    NASA Astrophysics Data System (ADS)

    Randorf, Jeffrey Allen

    2000-11-01

    A software object model for the six degree-of-freedom missile modeling domain is presented. As a precursor, a domain analysis of the missile modeling domain was started, based on the Feature-Oriented Domain Analysis (FODA) technique described by the Software Engineering Institute (SEI). It was subsequently determined the FODA methodology is functionally equivalent to the Object Modeling Technique. The analysis used legacy software documentation and code from the ENDOSIM, KDEC, and TFrames 6-DOF modeling tools, including other technical literature. The SEI Object Connection Architecture (OCA) was the template for designing the object model. Three variants of the OCA were considered---a reference structure, a recursive structure, and a reference structure with augmentation for flight vehicle modeling. The reference OCA design option was chosen for maintaining simplicity while not compromising the expressive power of the OMT model. The missile architecture was then analyzed for potential areas of concurrent computing. It was shown how protected objects could be used for data passing between OCA object managers, allowing concurrent access without changing the OCA reference design intent or structure. The implementation language was the 1995 release of Ada. OCA software components were shown how to be expressed as Ada child packages. While acceleration of several low level and other high operations level are possible on proper hardware, there was a 33% degradation of 4th order Runge-Kutta integrator performance of two simultaneous ordinary differential equations using Ada tasking on a single processor machine. The Defense Department's High Level Architecture was introduced and explained in context with the OCA. It was shown the HLA and OCA were not mutually exclusive architectures, but complimentary. HLA was shown as an interoperability solution, with the OCA as an architectural vehicle for software reuse. Further directions for implementing a 6-DOF missile modeling

  8. Simulation verification techniques study: Simulation self test hardware design and techniques report

    NASA Technical Reports Server (NTRS)

    1974-01-01

    The final results are presented of the hardware verification task. The basic objectives of the various subtasks are reviewed along with the ground rules under which the overall task was conducted and which impacted the approach taken in deriving techniques for hardware self test. The results of the first subtask and the definition of simulation hardware are presented. The hardware definition is based primarily on a brief review of the simulator configurations anticipated for the shuttle training program. The results of the survey of current self test techniques are presented. The data sources that were considered in the search for current techniques are reviewed, and results of the survey are presented in terms of the specific types of tests that are of interest for training simulator applications. Specifically, these types of tests are readiness tests, fault isolation tests and incipient fault detection techniques. The most applicable techniques were structured into software flows that are then referenced in discussions of techniques for specific subsystems.

  9. Design and application of implicit solvent models in biomolecular simulations

    PubMed Central

    Kleinjung, Jens; Fraternali, Franca

    2014-01-01

    We review implicit solvent models and their parametrisation by introducing the concepts and recent devlopments of the most popular models with a focus on parametrisation via force matching. An overview of recent applications of the solvation energy term in protein dynamics, modelling, design and prediction is given to illustrate the usability and versatility of implicit solvation in reproducing the physical behaviour of biomolecular systems. Limitations of implicit modes are discussed through the example of more challenging systems like nucleic acids and membranes. PMID:24841242

  10. Improved Space Charge Modeling for Simulation and Design of Photoinjectors

    SciTech Connect

    Robert H. Jackson, Thuc Bui, John Verboncoeur

    2010-04-19

    Photoinjectors in advanced high-energy accelerators reduce beam energy spreads and enhance undulator photon fluxes. Photoinjector design is difficult because of the substantial differences in time and spatial scales. This Phase I program explored an innovative technique, the local Taylor polynomial (LTP) formulation, for improving finite difference analysis of photoinjectors. This included improved weighting techniques, systematic formula for high order interpolation and electric field computation, and improved handling of space charge. The Phase I program demonstrated that the approach was powerful, accurate, and efficient. It handles space charge gradients better than currently available technology.

  11. Site–Specific Monoubiquitination Activates Ras by Impeding GTPase Activating Protein Function

    PubMed Central

    Baker, Rachael; Lewis, Steven M.; Sasaki, Atsuo T.; Wilkerson, Emily M.; Locasale, Jason W.; Cantley, Lewis C.; Kuhlman, Brian; Dohlman, Henrik G.; Campbell, Sharon L.

    2012-01-01

    SUMMARY Cell growth and differentiation are controlled by growth factor receptors coupled to the GTPase Ras. Oncogenic mutations disrupt GTPase activity leading to persistent Ras signaling and cancer progression. Recent evidence indicates that monoubiquitination of Ras leads to Ras activation. Mutation of the primary site of monoubiquitination impairs the ability of activated K–Ras to promote tumor growth. To determine the mechanism of human Ras activation we chemically ubiquitinated the protein and analyzed its function by NMR, computational modeling, and biochemical activity measurements. We established that monoubiquitination has little effect on Ras GTP binding, GTP hydrolysis, or exchange factor activation, but severely abrogates the response to GTPase activating proteins in a site–specific manner. These findings reveal a new mechanism by which Ras can trigger persistent signaling in the absence of receptor activation or an oncogenic mutation. PMID:23178454

  12. Design of a high-speed digital processing element for parallel simulation

    NASA Technical Reports Server (NTRS)

    Milner, E. J.; Cwynar, D. S.

    1983-01-01

    A prototype of a custom designed computer to be used as a processing element in a multiprocessor based jet engine simulator is described. The purpose of the custom design was to give the computer the speed and versatility required to simulate a jet engine in real time. Real time simulations are needed for closed loop testing of digital electronic engine controls. The prototype computer has a microcycle time of 133 nanoseconds. This speed was achieved by: prefetching the next instruction while the current one is executing, transporting data using high speed data busses, and using state of the art components such as a very large scale integration (VLSI) multiplier. Included are discussions of processing element requirements, design philosophy, the architecture of the custom designed processing element, the comprehensive instruction set, the diagnostic support software, and the development status of the custom design.

  13. Modeling and design optimization of switched reluctance machine by boundary element analysis and simulation

    SciTech Connect

    Tang, Y.; Kline, J.A. Sr.

    1996-12-01

    Nonlinear boundary element analysis provides a more accurate and detailing tool for the design of switched reluctance machines, than the conventional equivalent-circuit methods. Design optimization through more detailed analysis and simulation can reduce development and prototyping costs and time to market. Firstly, magnetic field modeling of an industrial switched reluctance machine by boundary element method is reported in this paper. Secondly, performance prediction and dynamic simulation of motor and control design are presented. Thirdly, magnetic forces that cause noise and vibration are studied, to include the effects of motor and control design variations on noise in the design process. Testing of the motor in NEMA 215-Frame size is carried out to verify the accuracy of modeling and simulation.

  14. Approximate simulation model for analysis and optimization in engineering system design

    NASA Technical Reports Server (NTRS)

    Sobieszczanski-Sobieski, Jaroslaw

    1989-01-01

    Computational support of the engineering design process routinely requires mathematical models of behavior to inform designers of the system response to external stimuli. However, designers also need to know the effect of the changes in design variable values on the system behavior. For large engineering systems, the conventional way of evaluating these effects by repetitive simulation of behavior for perturbed variables is impractical because of excessive cost and inadequate accuracy. An alternative is described based on recently developed system sensitivity analysis that is combined with extrapolation to form a model of design. This design model is complementary to the model of behavior and capable of direct simulation of the effects of design variable changes.

  15. Conversion of microalgae to jet fuel: process design and simulation.

    PubMed

    Wang, Hui-Yuan; Bluck, David; Van Wie, Bernard J

    2014-09-01

    Microalgae's aquatic, non-edible, highly genetically modifiable nature and fast growth rate are considered ideal for biomass conversion to liquid fuels providing promise for future shortages in fossil fuels and for reducing greenhouse gas and pollutant emissions from combustion. We demonstrate adaptability of PRO/II software by simulating a microalgae photo-bio-reactor and thermolysis with fixed conversion isothermal reactors adding a heat exchanger for thermolysis. We model a cooling tower and gas floatation with zero-duty flash drums adding solids removal for floatation. Properties data are from PRO/II's thermodynamic data manager. Hydrotreating is analyzed within PRO/II's case study option, made subject to Jet B fuel constraints, and we determine an optimal 6.8% bioleum bypass ratio, 230°C hydrotreater temperature, and 20:1 bottoms to overhead distillation ratio. Process economic feasibility occurs if cheap CO2, H2O and nutrient resources are available, along with solar energy and energy from byproduct combustion, and hydrotreater H2 from product reforming. PMID:24997379

  16. Simulation/optimization modeling for robust pumping strategy design.

    PubMed

    Kalwij, Ineke M; Peralta, Richard C

    2006-01-01

    A new simulation/optimization modeling approach is presented for addressing uncertain knowledge of aquifer parameters. The Robustness Enhancing Optimizer (REO) couples genetic algorithm and tabu search as optimizers and incorporates aquifer parameter sensitivity analysis to guide multiple-realization optimization. The REO maximizes strategy robustness for a pumping strategy that is optimal for a primary objective function (OF), such as cost. The more robust a strategy, the more likely it is to achieve management goals in the field, even if the physical system differs from the model. The REO is applied to trinitrotoluene and Royal Demolition Explosive plumes at Umatilla Chemical Depot in Oregon to develop robust least cost strategies. The REO efficiently develops robust pumping strategies while maintaining the optimal value of the primary OF-differing from the common situation in which a primary OF value degrades as strategy reliability increases. The REO is especially valuable where data to develop realistic probability density functions (PDFs) or statistically derived realizations are unavailable. Because they require much less field data, REO-developed strategies might not achieve as high a mathematical reliability as strategies developed using many realizations based upon real aquifer parameter PDFs. REO-developed strategies might or might not yield a better OF value in the field. PMID:16857035

  17. Design distributed simulation platform for vehicle management system

    NASA Astrophysics Data System (ADS)

    Wen, Zhaodong; Wang, Zhanlin; Qiu, Lihua

    2006-11-01

    Next generation military aircraft requires the airborne management system high performance. General modules, data integration, high speed data bus and so on are needed to share and manage information of the subsystems efficiently. The subsystems include flight control system, propulsion system, hydraulic power system, environmental control system, fuel management system, electrical power system and so on. The unattached or mixed architecture is changed to integrated architecture. That means the whole airborne system is regarded into one system to manage. So the physical devices are distributed but the system information is integrated and shared. The process function of each subsystem are integrated (including general process modules, dynamic reconfiguration), furthermore, the sensors and the signal processing functions are shared. On the other hand, it is a foundation for power shared. Establish a distributed vehicle management system using 1553B bus and distributed processors which can provide a validation platform for the research of airborne system integrated management. This paper establishes the Vehicle Management System (VMS) simulation platform. Discuss the software and hardware configuration and analyze the communication and fault-tolerant method.

  18. Synthetic tracked aperture ultrasound imaging: design, simulation, and experimental evaluation.

    PubMed

    Zhang, Haichong K; Cheng, Alexis; Bottenus, Nick; Guo, Xiaoyu; Trahey, Gregg E; Boctor, Emad M

    2016-04-01

    Ultrasonography is a widely used imaging modality to visualize anatomical structures due to its low cost and ease of use; however, it is challenging to acquire acceptable image quality in deep tissue. Synthetic aperture (SA) is a technique used to increase image resolution by synthesizing information from multiple subapertures, but the resolution improvement is limited by the physical size of the array transducer. With a large F-number, it is difficult to achieve high resolution in deep regions without extending the effective aperture size. We propose a method to extend the available aperture size for SA-called synthetic tracked aperture ultrasound (STRATUS) imaging-by sweeping an ultrasound transducer while tracking its orientation and location. Tracking information of the ultrasound probe is used to synthesize the signals received at different positions. Considering the practical implementation, we estimated the effect of tracking and ultrasound calibration error to the quality of the final beamformed image through simulation. In addition, to experimentally validate this approach, a 6 degree-of-freedom robot arm was used as a mechanical tracker to hold an ultrasound transducer and to apply in-plane lateral translational motion. Results indicate that STRATUS imaging with robotic tracking has the potential to improve ultrasound image quality. PMID:27088108

  19. Design, Simulation and Fabrication of Triaxial MEMS High Shock Accelerometer.

    PubMed

    Zhang, Zhenhai; Shi, Zhiguo; Yang, Zhan; Xie, Zhihong; Zhang, Donghong; Cai, De; Li, Kejie; Shen, Yajing

    2015-04-01

    On the basis of analyzing the disadvantage of other structural accelerometer, three-axis high g MEMS piezoresistive accelerometer was put forward in order to apply to the high-shock test field. The accelerometer's structure and working principle were discussed in details. The simulation results show that three-axis high shock MEMS accelerometer can bear high shock. After bearing high shock impact in high-shock shooting test, three-axis high shock MEMS accelerometer can obtain the intact metrical information of the penetration process and still guarantee the accurate precision of measurement in high shock load range, so we can not only analyze the law of stress wave spreading and the penetration rule of the penetration process of the body of the missile, but also furnish the testing technology of the burst point controlling. The accelerometer has far-ranging application in recording the typical data that projectile penetrating hard target and furnish both technology guarantees for penetration rule and defend engineering. PMID:26353519

  20. Nonlinear filtering in oil/gas reservoir simulation: filter design

    SciTech Connect

    Arnold, E.M.; Voss, D.A.; Mayer, D.W.

    1980-10-01

    In order to provide an additional mode of utility to the USGS reservoir model VARGOW, a nonlinear filter was designed and incorporated into the system. As a result, optimal (in the least squares sense) estimates of reservoir pressure, liquid mass, and gas cap plus free gas mass are obtained from an input of reservoir initial condition estimates and pressure history. These optimal estimates are provided continuously for each time after the initial time, and the input pressure history is allowed to be corrupted by measurement error. Preliminary testing of the VARGOW filter was begun and the results show promise. Synthetic data which could be readily manipulated during testing was used in tracking tests. The results were positive when the initial estimates of the reservoir initial conditions were reasonably close. Further testing is necessary to investigate the filter performance with real reservoir data.

  1. Compartmentalized Ras Proteins Transform NIH 3T3 Cells with Different Efficiencies▿ †

    PubMed Central

    Cheng, Chiang-Min; Li, Huiling; Gasman, Stéphane; Huang, Jian; Schiff, Rachel; Chang, Eric C.

    2011-01-01

    Ras GTPases were long thought to function exclusively from the plasma membrane (PM). However, a current model suggests that Ras proteins can compartmentalize to regulate different functions, and an oncogenic H-Ras mutant that is restricted to the endomembrane can still transform cells. In this study, we demonstrated that cells transformed by endomembrane-restricted oncogenic H-Ras formed tumors in nude mice. To define downstream targets of endomembrane Ras pathways, we analyzed Cdc42, which concentrates in the endomembrane and has been shown to act downstream of Ras in Schizosaccharomyces pombe. Our data show that cell transformation induced by endomembrane-restricted oncogenic H-Ras was blocked when Cdc42 activity was inhibited. Moreover, H-Ras formed a complex with Cdc42 on the endomembrane, and this interaction was enhanced when H-Ras was GTP bound or when cells were stimulated by growth factors. H-Ras binding evidently induced Cdc42 activation by recruiting and/or activating Cdc42 exchange factors. In contrast, when constitutively active H-Ras was restricted to the PM by fusing to a PM localization signal from the Rit GTPase, the resulting protein did not detectably activate Cdc42 although it activated Raf-1 and efficiently induced hallmarks of Ras-induced senescence in human BJ foreskin fibroblasts. Surprisingly, PM-restricted oncogenic Ras when expressed alone could only weakly transform NIH 3T3 cells; however, when constitutively active Cdc42 was coexpressed, together they transformed cells much more efficiently than either one alone. These data suggest that efficient cell transformation requires Ras proteins to interact with Cdc42 on the endomembrane and that in order for a given Ras protein to fully transform cells, multiple compartment-specific Ras pathways need to work cooperatively. PMID:21189290

  2. Design, simulation, fabrication, and characterization of MEMS vibration energy harvesters

    NASA Astrophysics Data System (ADS)

    Oxaal, John

    Energy harvesting from ambient sources has been a longtime goal for microsystem engineers. The energy available from ambient sources is substantial and could be used to power wireless micro devices, making them fully autonomous. Self-powered wireless sensors could have many applications in for autonomous monitoring of residential, commercial, industrial, geological, or biological environments. Ambient vibrations are of particular interest for energy harvesting as they are ubiquitous and have ample kinetic energy. In this work a MEMS device for vibration energy harvesting using a variable capacitor structure is presented. The nonlinear electromechanical dynamics of a gap-closing type structure is experimentally studied. Important experimental considerations such as the importance of reducing off-axis vibration during testing, characterization methods, dust contamination, and the effect of grounding on parasitic capacitance are discussed. A comprehensive physics based model is developed and validated with two different microfabricated devices. To achieve maximal power, devices with high aspect ratio electrodes and a novel two-level stopper system are designed and fabricated. The maximum achieved power from the MEMS device when driven by sinusoidal vibrations was 3.38 muW. Vibrations from HVAC air ducts, which have a primary frequency of 65 Hz and amplitude of 155 mgrms, are targeted as the vibration source and devices are designed for maximal power harvesting potential at those conditions. Harvesting from the air ducts, the devices reached 118 nW of power. When normalized to the operating conditions, the best figure of merit of the devices tested was an order of magnitude above state-of-the-art of the devices (1.24E-6).

  3. The role of simulation in the design of a neural network chip

    NASA Technical Reports Server (NTRS)

    Desai, Utpal; Roppel, Thaddeus A.; Padgett, Mary L.

    1993-01-01

    An iterative, simulation-based design procedure for a neural network chip is introduced. For this design procedure, the goal is to produce a chip layout for a neural network in which the weights are determined by transistor gate width-to-length ratios. In a given iteration, the current layout is simulated using the circuit simulator SPICE, and layout adjustments are made based on conventional gradient-decent methods. After the iteration converges, the chip is fabricated. Monte Carlo analysis is used to predict the effect of statistical fabrication process variations on the overall performance of the neural network chip.

  4. A graphical user interface for design, simulation and analysis of power plant electrical auxiliary systems

    SciTech Connect

    Yu, D.C.; Jamal, N.; Wang, W.; Zhang, X.G. ); Brandt, J.R. )

    1994-06-01

    An interactive Graphical User Interface (GUI) package for the design, simulation and analysis of a power plant electrical auxiliary system is presented in this paper. The purpose of this package is to assist the engineer in performing non real-time, what-if, analysis in an interactive and intuitive environment. The package, AUXSYS, is capable of performing load flow and motor starting simulations. It provides a graphical interface for designing the one-line diagram of the plant and analyzing the output of the simulations. It is currently used for modeling Wisconsin Electric Power Company's (WEPCO) power plant electrical auxiliary systems and is implemented for use on PC's.

  5. A Novel Simulation Technician Laboratory Design: Results of a Survey-Based Study

    PubMed Central

    Hughes, Patrick G; Friedl, Ed; Ortiz Figueroa, Fabiana; Cepeda Brito, Jose R; Frey, Jennifer; Birmingham, Lauren E; Atkinson, Steven Scott

    2016-01-01

    Objective  The purpose of this study was to elicit feedback from simulation technicians prior to developing the first simulation technician-specific simulation laboratory in Akron, OH. Background Simulation technicians serve a vital role in simulation centers within hospitals/health centers around the world. The first simulation technician degree program in the US has been approved in Akron, OH. To satisfy the requirements of this program and to meet the needs of this special audience of learners, a customized simulation lab is essential.  Method A web-based survey was circulated to simulation technicians prior to completion of the lab for the new program. The survey consisted of questions aimed at identifying structural and functional design elements of a novel simulation center for the training of simulation technicians. Quantitative methods were utilized to analyze data. Results Over 90% of technicians (n=65) think that a lab designed explicitly for the training of technicians is novel and beneficial. Approximately 75% of respondents think that the space provided appropriate audiovisual (AV) infrastructure and space to evaluate the ability of technicians to be independent. The respondents think that the lab needed more storage space, visualization space for a large number of students, and more space in the technical/repair area. Conclusions  A space designed for the training of simulation technicians was considered to be beneficial. This laboratory requires distinct space for technical repair, adequate bench space for the maintenance and repair of simulators, an appropriate AV infrastructure, and space to evaluate the ability of technicians to be independent. PMID:27096134

  6. Genomic classification of the RAS network identifies a personalized treatment strategy for lung cancer

    PubMed Central

    El-Chaar, Nader N.; Piccolo, Stephen R.; Boucher, Kenneth M.; Cohen, Adam L.; Chang, Jeffrey T.; Moos, Philip J.; Bild, Andrea H.

    2014-01-01

    Better approaches are needed to evaluate a single patient's drug response at the genomic level. Targeted therapy for signaling pathways in cancer has met limited success in part due to the exceedingly interwoven nature of the pathways. In particular, the highly complex RAS network has been challenging to target. Effectively targeting the pathway requires development of techniques that measure global network activity to account for pathway complexity. For this purpose, we used a gene-expression-based biomarker for RAS network activity in non-small cell lung cancer (NSCLC) cells, and screened for drugs whose efficacy were significantly highly correlated to RAS network activity. Results identified EGFR and MEK co-inhibition as the most effective treatment for RAS-active NSCLC amongst a panel of over 360 compounds and fractions. RAS activity was identified in both RAS-mutant and wild-type lines, indicating broad characterization of RAS signaling inclusive of multiple mechanisms of RAS activity, and not solely based on mutation status. Mechanistic studies demonstrated that co-inhibition of EGFR and MEK induced apoptosis and blocked both EGFR-RAS-RAF-MEK-ERK and EGFR-PI3K-AKT-RPS6 nodes simultaneously in RAS-active, but not RAS-inactive NSCLC. These results provide a comprehensive strategy to personalize treatment of NSCLC based on RAS network dysregulation and provide proof-of-concept of a genomic approach to classify and target complex signaling networks. PMID:24908424

  7. Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function.

    PubMed

    Hocker, Harrison J; Cho, Kwang-Jin; Chen, Chung-Ying K; Rambahal, Nandini; Sagineedu, Sreenivasa Rao; Shaari, Khozirah; Stanslas, Johnson; Hancock, John F; Gorfe, Alemayehu A

    2013-06-18

    Aberrant signaling by oncogenic mutant rat sarcoma (Ras) proteins occurs in ∼15% of all human tumors, yet direct inhibition of Ras by small molecules has remained elusive. Recently, several small-molecule ligands have been discovered that directly bind Ras and inhibit its function by interfering with exchange factor binding. However, it is unclear whether, or how, these ligands could lead to drugs that act against constitutively active oncogenic mutant Ras. Using a dynamics-based pocket identification scheme, ensemble docking, and innovative cell-based assays, here we show that andrographolide (AGP)--a bicyclic diterpenoid lactone isolated from Andrographis paniculata--and its benzylidene derivatives bind to transient pockets on Kirsten-Ras (K-Ras) and inhibit GDP-GTP exchange. As expected for inhibitors of exchange factor binding, AGP derivatives reduced GTP loading of wild-type K-Ras in response to acute EGF stimulation with a concomitant reduction in MAPK activation. Remarkably, however, prolonged treatment with AGP derivatives also reduced GTP loading of, and signal transmission by, oncogenic mutant K-RasG12V. In sum, the combined analysis of our computational and cell biology results show that AGP derivatives directly bind Ras, block GDP-GTP exchange, and inhibit both wild-type and oncogenic K-Ras signaling. Importantly, our findings not only show that nucleotide exchange factors are required for oncogenic Ras signaling but also demonstrate that inhibiting nucleotide exchange is a valid approach to abrogating the function of oncogenic mutant Ras. PMID:23737504

  8. Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

    PubMed Central

    Hocker, Harrison J.; Cho, Kwang-Jin; Chen, Chung-Ying K.; Rambahal, Nandini; Sagineedu, Sreenivasa Rao; Shaari, Khozirah; Stanslas, Johnson; Hancock, John F.; Gorfe, Alemayehu A.

    2013-01-01

    Aberrant signaling by oncogenic mutant rat sarcoma (Ras) proteins occurs in ∼15% of all human tumors, yet direct inhibition of Ras by small molecules has remained elusive. Recently, several small-molecule ligands have been discovered that directly bind Ras and inhibit its function by interfering with exchange factor binding. However, it is unclear whether, or how, these ligands could lead to drugs that act against constitutively active oncogenic mutant Ras. Using a dynamics-based pocket identification scheme, ensemble docking, and innovative cell-based assays, here we show that andrographolide (AGP)—a bicyclic diterpenoid lactone isolated from Andrographis paniculata—and its benzylidene derivatives bind to transient pockets on Kirsten-Ras (K-Ras) and inhibit GDP–GTP exchange. As expected for inhibitors of exchange factor binding, AGP derivatives reduced GTP loading of wild-type K-Ras in response to acute EGF stimulation with a concomitant reduction in MAPK activation. Remarkably, however, prolonged treatment with AGP derivatives also reduced GTP loading of, and signal transmission by, oncogenic mutant K-RasG12V. In sum, the combined analysis of our computational and cell biology results show that AGP derivatives directly bind Ras, block GDP–GTP exchange, and inhibit both wild-type and oncogenic K-Ras signaling. Importantly, our findings not only show that nucleotide exchange factors are required for oncogenic Ras signaling but also demonstrate that inhibiting nucleotide exchange is a valid approach to abrogating the function of oncogenic mutant Ras. PMID:23737504

  9. Bibliography of Selected SCSD, URBS, SSP, SEF, and RAS Publications.

    ERIC Educational Resources Information Center

    Stanford Univ., CA. School Planning Lab.

    The annotated bibliography contains publications and report listings of the following sources--(1) School Construction Systems Development (SCSD), (2) University Residential Building Systems (URBS), (3) Florida Schoolhouse Systems Project (SSP), (4) Study of Educational Facilities (SEF), and (5) Recherches en Amenagements Scolaires (RAS) Building…

  10. DSC: software tool for simulation-based design of control strategies applied to wastewater treatment plants.

    PubMed

    Ruano, M V; Ribes, J; Seco, A; Ferrer, J

    2011-01-01

    This paper presents a computer tool called DSC (Simulation based Controllers Design) that enables an easy design of control systems and strategies applied to wastewater treatment plants. Although the control systems are developed and evaluated by simulation, this tool aims to facilitate the direct implementation of the designed control system to the PC of the full-scale WWTP (wastewater treatment plants). The designed control system can be programmed in a dedicated control application and can be connected to either the simulation software or the SCADA of the plant. To this end, the developed DSC incorporates an OPC server (OLE for process control) which facilitates an open-standard communication protocol for different industrial process applications. The potential capabilities of the DSC tool are illustrated through the example of a full-scale application. An aeration control system applied to a nutrient removing WWTP was designed, tuned and evaluated with the DSC tool before its implementation in the full scale plant. The control parameters obtained by simulation were suitable for the full scale plant with only few modifications to improve the control performance. With the DSC tool, the control systems performance can be easily evaluated by simulation. Once developed and tuned by simulation, the control systems can be directly applied to the full-scale WWTP. PMID:21330730

  11. The Interior Design Simulator. Courseware Evaluation for Vocational and Technical Education.

    ERIC Educational Resources Information Center

    Worts, Nancy; And Others

    This courseware evaluation rates the Interior Design Simulator program developed by Orange Juice Software Systems. (This program--not contained in this document--allows the user to design a room of any shape with maximum dimensions of 14 x 26 feet.) Part A describes the program in terms of subject area (furniture arrangement) and hardware…

  12. Assessing the Effectiveness of a Computer Simulation for Teaching Ecological Experimental Design

    ERIC Educational Resources Information Center

    Stafford, Richard; Goodenough, Anne E.; Davies, Mark S.

    2010-01-01

    Designing manipulative ecological experiments is a complex and time-consuming process that is problematic to teach in traditional undergraduate classes. This study investigates the effectiveness of using a computer simulation--the Virtual Rocky Shore (VRS)--to facilitate rapid, student-centred learning of experimental design. We gave a series of…

  13. A Simulation-Based LED Design Project in Photonics Instruction Based on Industry-University Collaboration

    ERIC Educational Resources Information Center

    Chang, S. -H.; Chen, M. -L.; Kuo, Y. -K.; Shen, Y. -C.

    2011-01-01

    In response to the growing industrial demand for light-emitting diode (LED) design professionals, based on industry-university collaboration in Taiwan, this paper develops a novel instructional approach: a simulation-based learning course with peer assessment to develop students' professional skills in LED design as required by industry as well as…

  14. Using R to Simulate Permutation Distributions for Some Elementary Experimental Designs

    ERIC Educational Resources Information Center

    Eudey, T. Lynn; Kerr, Joshua D.; Trumbo, Bruce E.

    2010-01-01

    Null distributions of permutation tests for two-sample, paired, and block designs are simulated using the R statistical programming language. For each design and type of data, permutation tests are compared with standard normal-theory and nonparametric tests. These examples (often using real data) provide for classroom discussion use of metrics…

  15. Fractal Simulations of African Design in Pre-College Computing Education

    ERIC Educational Resources Information Center

    Eglash, Ron; Krishnamoorthy, Mukkai; Sanchez, Jason; Woodbridge, Andrew

    2011-01-01

    This article describes the use of fractal simulations of African design in a high school computing class. Fractal patterns--repetitions of shape at multiple scales--are a common feature in many aspects of African design. In African architecture we often see circular houses grouped in circular complexes, or rectangular houses in rectangular…

  16. The simulative calculation and optimum design for FOA, the purge gas sweeping system

    NASA Astrophysics Data System (ADS)

    Wang, Liquan; Jing, Yukun; Feng, Bing; Li, Fuquan; Xiang, Yong; Han, Wei; Wang, Fang

    2016-01-01

    This paper first studies the structure effect law in order to design a reasonable option in theory for the Final Optics Assembly(FOA)' harmonic converter module, involved in the design of the fluid theory, including the basic equations of fluid motion, the form of fluid motion and fluid movement in the small hole. Optimizing the structure need to be applied to the simulation software, which requires the Fluent simulation principle. Then, combined with theoretical knowledge to design the overall structure of the multiplier module, It will apply the simulation software to optimize structural parameters of the board and use control system to realize it for verifying the law obtained by simulation under various conditions whether consistent with the law in actual work of the sweeping system.

  17. Interim Service ISDN Satellite (ISIS) simulator development for advanced satellite designs and experiments

    NASA Technical Reports Server (NTRS)

    Pepin, Gerard R.

    1992-01-01

    The simulation development associated with the network models of both the Interim Service Integrated Services Digital Network (ISDN) Satellite (ISIS) and the Full Service ISDN Satellite (FSIS) architectures is documented. The ISIS Network Model design represents satellite systems like the Advanced Communications Technology Satellite (ACTS) orbiting switch. The FSIS architecture, the ultimate aim of this element of the Satellite Communications Applications Research (SCAR) Program, moves all control and switching functions on-board the next generation ISDN communications satellite. The technical and operational parameters for the advanced ISDN communications satellite design will be obtained from the simulation of ISIS and FSIS engineering software models for their major subsystems. Discrete event simulation experiments will be performed with these models using various traffic scenarios, design parameters, and operational procedures. The data from these simulations will be used to determine the engineering parameters for the advanced ISDN communications satellite.

  18. Washout circuit design for multi-degrees-of-freedom moving base simulators.

    NASA Technical Reports Server (NTRS)

    Conrad, B.; Schmidt, S. F.; Douvillier, J. G.

    1973-01-01

    A mathematical framework is presented for designing logic to accept motion-dependent parameters from a simulation, attenuating them ('washing them out'), and generating appropriately limited drive signals. This framework is sufficiently general to encompass six-degree-of-freedom simulators with large motion capability. Emphasis is placed on preserving certain motion cue relations (such as those that would be observed in coordinated flight). Strategies for simulating side forces via tilts are shown. Finally, several specific circuits are shown. These circuits have proven to be readily adaptable to a variety of moving-base simulators.

  19. Design data package and operating procedures for MSFC solar simulator test facility

    NASA Technical Reports Server (NTRS)

    1981-01-01

    Design and operational data for the solar simulator test facility are reviewed. The primary goal of the facility is to evaluate the performance capacibility and worst case failure modes of collectors, which utilize either air or liquid transport media. The facility simulates environmental parameters such as solar radiation intensity, solar spectrum, collimation, uniformity, and solar attitude. The facility also simulates wind conditions of velocity and direction, solar system conditions imposed on the collector, collector fluid inlet temperature, and geometric factors of collector tilt and azimuth angles. Testing the simulator provides collector efficiency data, collector time constant, incident angle modifier data, and stagnation temperature values.

  20. An optimal control approach to the design of moving flight simulators

    NASA Technical Reports Server (NTRS)

    Sivan, R.; Ish-Shalom, J.; Huang, J.-K.

    1982-01-01

    An abstract flight simulator design problem is formulated in the form of an optimal control problem, which is solved for the linear-quadratic-Gaussian special case using a mathematical model of the vestibular organs. The optimization criterion used is the mean-square difference between the physiological outputs of the vestibular organs of the pilot in the aircraft and the pilot in the simulator. The dynamical equations are linearized, and the output signal is modeled as a random process with rational power spectral density. The method described yields the optimal structure of the simulator's motion generator, or 'washout filter'. A two-degree-of-freedom flight simulator design, including single output simulations, is presented.

  1. Nuclear power plant human computer interface design incorporating console simulation, operations personnel, and formal evaluation techniques

    SciTech Connect

    Chavez, C.; Edwards, R.M.; Goldberg, J.H.

    1993-12-31

    New CRT-based information displays which enhance the human machine interface are playing a very important role and are being increasingly used in control rooms since they present a higher degree of flexibility compared to conventional hardwired instrumentation. To prototype a new console configuration and information display system at the Experimental Breeder Reactor II (EBR-II), an iterative process of console simulation and evaluation involving operations personnel is being pursued. Entire panels including selector switches and information displays are simulated and driven by plant dynamical simulations with realistic responses that reproduce the actual cognitive and physical environment. Careful analysis and formal evaluation of operator interaction while using the simulated console will be conducted to determine underlying principles for effective control console design for this particular group of operation personnel. Additional iterations of design, simulation, and evaluation will then be conducted as necessary.

  2. Modeling, simulation, and concept design for hybrid-electric medium-size military trucks

    NASA Astrophysics Data System (ADS)

    Rizzoni, Giorgio; Josephson, John R.; Soliman, Ahmed; Hubert, Christopher; Cantemir, Codrin-Gruie; Dembski, Nicholas; Pisu, Pierluigi; Mikesell, David; Serrao, Lorenzo; Russell, James; Carroll, Mark

    2005-05-01

    A large scale design space exploration can provide valuable insight into vehicle design tradeoffs being considered for the U.S. Army"s FMTV (Family of Medium Tactical Vehicles). Through a grant from TACOM (Tank-automotive and Armaments Command), researchers have generated detailed road, surface, and grade conditions representative of the performance criteria of this medium-sized truck and constructed a virtual powertrain simulator for both conventional and hybrid variants. The simulator incorporates the latest technology among vehicle design options, including scalable ultracapacitor and NiMH battery packs as well as a variety of generator and traction motor configurations. An energy management control strategy has also been developed to provide efficiency and performance. A design space exploration for the family of vehicles involves running a large number of simulations with systematically varied vehicle design parameters, where each variant is paced through several different mission profiles and multiple attributes of performance are measured. The resulting designs are filtered to remove dominated designs, exposing the multi-criterial surface of optimality (Pareto optimal designs), and revealing the design tradeoffs as they impact vehicle performance and economy. The results are not yet definitive because ride and drivability measures were not included, and work is not finished on fine-tuning the modeled dynamics of some powertrain components. However, the work so far completed demonstrates the effectiveness of the approach to design space exploration, and the results to date suggest the powertrain configuration best suited to the FMTV mission.

  3. CLARREO shortwave observing system simulation experiments of the twenty-first century: Simulator design and implementation

    SciTech Connect

    Feldman, D.R.; Algieri, C.A.; Ong, J.R.; Collins, W.D.

    2011-04-01

    Projected changes in the Earth system will likely be manifested in changes in reflected solar radiation. This paper introduces an operational Observational System Simulation Experiment (OSSE) to calculate the signals of future climate forcings and feedbacks in top-of-atmosphere reflectance spectra. The OSSE combines simulations from the Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report for the NCAR Community Climate System Model (CCSM) with the MODTRAN radiative transfer code to calculate reflectance spectra for simulations of current and future climatic conditions over the 21st century. The OSSE produces narrowband reflectances and broadband fluxes, the latter of which have been extensively validated against archived CCSM results. The shortwave reflectance spectra contain atmospheric features including signals from water vapor, liquid and ice clouds, and aerosols. The spectra are also strongly influenced by the surface bidirectional reflectance properties of predicted snow and sea ice and the climatological seasonal cycles of vegetation. By comparing and contrasting simulated reflectance spectra based on emissions scenarios with increasing projected and fixed present-day greenhouse gas and aerosol concentrations, we find that prescribed forcings from increases in anthropogenic sulfate and carbonaceous aerosols are detectable and are spatially confined to lower latitudes. Also, changes in the intertropical convergence zone and poleward shifts in the subsidence zones and the storm tracks are all detectable along with large changes in snow cover and sea ice fraction. These findings suggest that the proposed NASA Climate Absolute Radiance and Refractivity Observatory (CLARREO) mission to measure shortwave reflectance spectra may help elucidate climate forcings, responses, and feedbacks.

  4. CLARREO shortwave observing system simulation experiments of the twenty-first century: Simulator design and implementation

    NASA Astrophysics Data System (ADS)

    Feldman, Daniel R.; Algieri, Chris A.; Ong, Jonathan R.; Collins, William D.

    2011-05-01

    Projected changes in the Earth system will likely be manifested in changes in reflected solar radiation. This paper introduces an operational Observational System Simulation Experiment (OSSE) to calculate the signals of future climate forcings and feedbacks in top-of-atmosphere reflectance spectra. The OSSE combines simulations from the Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report for the NCAR Community Climate System Model (CCSM) with the MODTRAN radiative transfer code to calculate reflectance spectra for simulations of current and future climatic conditions over the 21st century. The OSSE produces narrowband reflectances and broadband fluxes, the latter of which have been extensively validated against archived CCSM results. The shortwave reflectance spectra contain atmospheric features including signals from water vapor, liquid and ice clouds, and aerosols. The spectra are also strongly influenced by the surface bidirectional reflectance properties of predicted snow and sea ice and the climatological seasonal cycles of vegetation. By comparing and contrasting simulated reflectance spectra based on emissions scenarios with increasing projected and fixed present-day greenhouse gas and aerosol concentrations, we find that prescribed forcings from increases in anthropogenic sulfate and carbonaceous aerosols are detectable and are spatially confined to lower latitudes. Also, changes in the intertropical convergence zone and poleward shifts in the subsidence zones and the storm tracks are all detectable along with large changes in snow cover and sea ice fraction. These findings suggest that the proposed NASA Climate Absolute Radiance and Refractivity Observatory (CLARREO) mission to measure shortwave reflectance spectra may help elucidate climate forcings, responses, and feedbacks.

  5. Enhancing the energy-efficient design of office buildings using a based-simulation design support system

    NASA Astrophysics Data System (ADS)

    Kassab, Mohamed Samy Moawad

    This thesis presents a comprehensive study for enhancing the energy efficiency of office buildings in Canada. Two models were used: the thermal model to develop the thermal-related alternatives, and the daylighting model to explore means for more effectively exploiting daylight in buildings through extending periods of illumination free from glare problems. The key concept is to quantify and examine the impact of developed design parameters on the buildings' performance. The University of Calgary's Information and Communication Technology (ICT) office building is used as a base model for which the innovative techniques are developed and presented in this study. Although simulation programs can evaluate the illuminance levels and energy consumption of buildings, they are predicting programs rather than optimizing tools. Moreover, the concept of energy efficiency includes more than the total energy consumption; therefore, the Simulation-Based Design Support System (SBDSS) was developed to decide on the optimum design solutions for office buildings. The SBDSS was established using the C++ program and based on the simulation results of the EnergyPlus and Desktop Radiance software programs. The thermal and daylighting models were developed first; then, the SBDSS automatically modified the design parameters of models according to information provided by users. A database was created that includes the entire simulation results, comprising a large number of design solutions. The alternatives include the variations of individual parameters and the available combinations among such parameters composing multi-dimensional groups. The evaluation of the design alternatives was based on the life-cycle approach. Three objective functions were used in this analysis, including the total energy consumption; life-cycle cost; and environmental impacts, evaluated in terms of the equivalent CO2 emissions. A selection tool, developed by Excel, was used to derive the optimum alternatives

  6. MEMS 3-DoF gyroscope design, modeling and simulation through equivalent circuit lumped parameter model

    SciTech Connect

    Mian, Muhammad Umer Khir, M. H. Md.; Tang, T. B.; Dennis, John Ojur; Riaz, Kashif; Iqbal, Abid; Bazaz, Shafaat A.

    2015-07-22

    Pre-fabrication, behavioural and performance analysis with computer aided design (CAD) tools is a common and fabrication cost effective practice. In light of this we present a simulation methodology for a dual-mass oscillator based 3 Degree of Freedom (3-DoF) MEMS gyroscope. 3-DoF Gyroscope is modeled through lumped parameter models using equivalent circuit elements. These equivalent circuits consist of elementary components which are counterpart of their respective mechanical components, used to design and fabricate 3-DoF MEMS gyroscope. Complete designing of equivalent circuit model, mathematical modeling and simulation are being presented in this paper. Behaviors of the equivalent lumped models derived for the proposed device design are simulated in MEMSPRO T-SPICE software. Simulations are carried out with the design specifications following design rules of the MetalMUMPS fabrication process. Drive mass resonant frequencies simulated by this technique are 1.59 kHz and 2.05 kHz respectively, which are close to the resonant frequencies found by the analytical formulation of the gyroscope. The lumped equivalent circuit modeling technique proved to be a time efficient modeling technique for the analysis of complex MEMS devices like 3-DoF gyroscopes. The technique proves to be an alternative approach to the complex and time consuming couple field analysis Finite Element Analysis (FEA) previously used.

  7. MEMS 3-DoF gyroscope design, modeling and simulation through equivalent circuit lumped parameter model

    NASA Astrophysics Data System (ADS)

    Mian, Muhammad Umer; Dennis, John Ojur; Khir, M. H. Md.; Riaz, Kashif; Iqbal, Abid; Bazaz, Shafaat A.; Tang, T. B.

    2015-07-01

    Pre-fabrication, behavioural and performance analysis with computer aided design (CAD) tools is a common and fabrication cost effective practice. In light of this we present a simulation methodology for a dual-mass oscillator based 3 Degree of Freedom (3-DoF) MEMS gyroscope. 3-DoF Gyroscope is modeled through lumped parameter models using equivalent circuit elements. These equivalent circuits consist of elementary components which are counterpart of their respective mechanical components, used to design and fabricate 3-DoF MEMS gyroscope. Complete designing of equivalent circuit model, mathematical modeling and simulation are being presented in this paper. Behaviors of the equivalent lumped models derived for the proposed device design are simulated in MEMSPRO T-SPICE software. Simulations are carried out with the design specifications following design rules of the MetalMUMPS fabrication process. Drive mass resonant frequencies simulated by this technique are 1.59 kHz and 2.05 kHz respectively, which are close to the resonant frequencies found by the analytical formulation of the gyroscope. The lumped equivalent circuit modeling technique proved to be a time efficient modeling technique for the analysis of complex MEMS devices like 3-DoF gyroscopes. The technique proves to be an alternative approach to the complex and time consuming couple field analysis Finite Element Analysis (FEA) previously used.

  8. Developing a workstation-based, real-time simulation for rapid handling qualities evaluations during design

    NASA Technical Reports Server (NTRS)

    Anderson, Frederick; Biezad, Daniel J.

    1994-01-01

    This paper describes the Rapid Aircraft DynamIcs AssessmeNt (RADIAN) project - an integration of the Aircraft SYNThesis (ACSTNT) design code with the USAD DATCOM code that estimates stability derivatives. Both of these codes are available to universities. These programs are then linked to flight simulation and flight controller synthesis tools and resulting design is evaluated on a graphics workstation. The entire process reduces the preliminary design time by an order of magnitude and provides an initial handling qualities evaluation of the design coupled to a control law. The integrated design process is applicable to both conventional aircraft taken from current textbooks and to unconventional designs emphasizing agility and propulsive control of attitude. The interactive and concurrent nature of the design process has been well received by industry and by design engineers at NASA. The process is being implemented into the design curriculum and is being used by students who view it as a significant advance over prior methods.

  9. Integrated layout based Monte-Carlo simulation for design arc optimization

    NASA Astrophysics Data System (ADS)

    Shao, Dongbing; Clevenger, Larry; Zhuang, Lei; Liebmann, Lars; Wong, Robert; Culp, James

    2016-03-01

    Design rules are created considering a wafer fail mechanism with the relevant design levels under various design cases, and the values are set to cover the worst scenario. Because of the simplification and generalization, design rule hinders, rather than helps, dense device scaling. As an example, SRAM designs always need extensive ground rule waivers. Furthermore, dense design also often involves "design arc", a collection of design rules, the sum of which equals critical pitch defined by technology. In design arc, a single rule change can lead to chain reaction of other rule violations. In this talk we present a methodology using Layout Based Monte-Carlo Simulation (LBMCS) with integrated multiple ground rule checks. We apply this methodology on SRAM word line contact, and the result is a layout that has balanced wafer fail risks based on Process Assumptions (PAs). This work was performed at the IBM Microelectronics Div, Semiconductor Research and Development Center, Hopewell Junction, NY 12533

  10. Design and simulation of a cable-pulley-based transmission for artificial ankle joints

    NASA Astrophysics Data System (ADS)

    Liu, Huaxin; Ceccarelli, Marco; Huang, Qiang

    2016-05-01

    In this paper, a mechanical transmission based on cable pulley is proposed for human-like actuation in the artificial ankle joints of human-scale. The anatomy articular characteristics of the human ankle is discussed for proper biomimetic inspiration in designing an accurate, efficient, and robust motion control of artificial ankle joint devices. The design procedure is presented through the inclusion of conceptual considerations and design details for an interactive solution of the transmission system. A mechanical design is elaborated for the ankle joint angular with pitch motion. A multi-body dynamic simulation model is elaborated accordingly and evaluated numerically in the ADAMS environment. Results of the numerical simulations are discussed to evaluate the dynamic performance of the proposed design solution and to investigate the feasibility of the proposed design in future applications for humanoid robots.

  11. Simulation Results for the New NSTX HHFW Antenna Straps Design by Using Microwave Studio

    SciTech Connect

    Kung, C C; Brunkhorst, C; Greenough, N; Fredd, E; Castano, A; Miller, D; D'Amico, G; Yager, R; Hosea, J; Wilson, J R; Ryan, P

    2009-05-26

    Experimental results have shown that the high harmonic fast wave (HHFW) at 30 MHz can provide substantial plasma heating and current drive for the NSTX spherical tokamak operation. However, the present antenna strap design rarely achieves the design goal of delivering the full transmitter capability of 6 MW to the plasma. In order to deliver more power to the plasma, a new antenna strap design and the associated coaxial line feeds are being constructed. This new antenna strap design features two feedthroughs to replace the old single feed-through design. In the design process, CST Microwave Studio has been used to simulate the entire new antenna strap structure including the enclosure and the Faraday shield. In this paper, the antenna strap model and the simulation results will be discussed in detail. The test results from the new antenna straps with their associated resonant loops will be presented as well.

  12. Behavioral modeling and simulation for the design process of aerospatial micro-instrumentation based on MEMS

    NASA Astrophysics Data System (ADS)

    Barrachina, L.; Lorente, B.; Ferrer, C.

    2006-05-01

    The extended use of microelectromechanical systems (MEMS) in the development of new microinstrumentation for aerospatial applications, which combine extreme sensitivity, accuracy and compactness, introduced the need to simplify their design process in order to reduce the design time and cost. The recent apparition of analogue and mixed signal extensions of hardware descriptions languages (VHDL-AMS, Verilog-AMS and SystemC-AMS) permits to co-simulate the HDL (VHDL and Verilog) design models for the digital signal processing and communication circuitry with behavioral models for the non digital parts (analog and mixed signal processing, RF circuitry and MEMS components). Since the beginning of the microinstrumentation design process the modeling and simulation could help to define better the specifications and in the architecture selection and in the SoC design process in a more realistic environment. We will present our experience in the application of these languages in the design of microinstruments by using behavioral modeling of MEMS.

  13. Design and simulation of a cable-pulley-based transmission for artificial ankle joints

    NASA Astrophysics Data System (ADS)

    Liu, Huaxin; Ceccarelli, Marco; Huang, Qiang

    2016-06-01

    In this paper, a mechanical transmission based on cable pulley is proposed for human-like actuation in the artificial ankle joints of human-scale. The anatomy articular characteristics of the human ankle is discussed for proper biomimetic inspiration in designing an accurate, efficient, and robust motion control of artificial ankle joint devices. The design procedure is presented through the inclusion of conceptual considerations and design details for an interactive solution of the transmission system. A mechanical design is elaborated for the ankle joint angular with pitch motion. A multi-body dynamic simulation model is elaborated accordingly and evaluated numerically in the ADAMS environment. Results of the numerical simulations are discussed to evaluate the dynamic performance of the proposed design solution and to investigate the feasibility of the proposed design in future applications for humanoid robots.

  14. Performance of McRAS-AC in the GEOS-5 AGCM: Part 1, Aerosol-Activated Cloud Microphysics, Precipitation, Radiative Effects, and Circulation

    NASA Technical Reports Server (NTRS)

    Sud, Y. C.; Lee, D.; Oreopoulos, L.; Barahona, D.; Nenes, A.; Suarez, M. J.

    2012-01-01

    A revised version of the Microphysics of clouds with Relaxed Arakawa-Schubert and Aerosol-Cloud interaction (McRAS-AC), including, among others, the Barahona and Nenes ice nucleation parameterization, is implemented in the GEOS-5 AGCM. Various fields from a 10-year long integration of the AGCM with McRAS-AC were compared with their counterparts from an integration of the baseline GEOS-5 AGCM, and with satellite data as observations. Generally using McRAS-AC reduced biases in cloud fields and cloud radiative effects are much better over most of the regions of the Earth. Two weaknesses are identified in the McRAS-AC runs, namely, too few cloud particles around 40S-60S, and too high cloud water path during northern hemisphere summer over the Gulf Stream and North Pacific. Sensitivity analyses showed that these biases potentially originated from biases in the aerosol input. The first bias is largely eliminated in a sensitivity test using 50% smaller aerosol particles, while the second bias is much reduced when interactive aerosol chemistry was turned on. The main drawback of McRAS-AC is dearth of low-level marine stratus clouds, probably due to lack of dry-convection, not yet implemented into the cloud scheme. Despite these biases, McRAS-AC does simulate realistic clouds and their optical properties that can improve with better aerosol-input and thereby has the potential to be a valuable tool for climate modeling research because of its aerosol indirect effect simulation capabilities involving prediction of cloud particle number concentration and effective particle size for both convective and stratiform clouds is quite realistic.

  15. NF2 loss promotes oncogenic RAS-induced thyroid cancers via YAP-dependent transactivation of RAS proteins and sensitizes them to MEK inhibition

    PubMed Central

    Garcia-Rendueles, Maria E.R.; Ricarte-Filho, Julio C.; Untch, Brian R.; Landa, Iňigo; Knauf, Jeffrey A.; Voza, Francesca; Smith, Vicki E.; Ganly, Ian; Taylor, Barry S.; Persaud, Yogindra; Oler, Gisele; Fang, Yuqiang; Jhanwar, Suresh C.; Viale, Agnes; Heguy, Adriana; Huberman, Kety H.; Giancotti, Filippo; Ghossein, Ronald; Fagin, James A.

    2015-01-01

    Ch22q LOH is preferentially associated with RAS mutations in papillary and in poorly differentiated thyroid cancer (PDTC). The 22q tumor suppressor NF2, encoding merlin, is implicated in this interaction because of its frequent loss of function in human thyroid cancer cell lines. Nf2 deletion or Hras mutation are insufficient for transformation, whereas their combined disruption leads to murine PDTC with increased MAPK signaling. Merlin loss induces RAS signaling in part through inactivation of Hippo, which activates a YAP-TEAD transcriptional program. We find that the three RAS genes are themselves YAP-TEAD1 transcriptional targets, providing a novel mechanism of promotion of RAS-induced tumorigenesis. Moreover, pharmacological disruption of YAP-TEAD with verteporfin blocks RAS transcription and signaling, and inhibits cell growth. The increased MAPK output generated by NF2 loss in RAS-mutant cancers may inform therapeutic strategies, as it generates greater dependency on the MAPK pathway for viability. PMID:26359368

  16. Design, Test, Redesign: Simulation in Technology, Engineering, and Design Education Classrooms

    ERIC Educational Resources Information Center

    Swinson, Ronnie; Clark, Aaron C.; Ernst, Jeremy V.; Sutton, Kevin

    2016-01-01

    Today's engineers, designers, and technologists are often thrust into the role of problem solver, from the initial design phase of a product or process all the way to final development. Many engineers in manufacturing environments are tasked with solving problems and continuously improving processes to enhance company profitability, efficiency,…

  17. Design study to simulate the development of a commercial transportation system

    NASA Technical Reports Server (NTRS)

    1991-01-01

    Seven teams of senior-level Aerospace Engineering undergraduates were given a Request for Proposals (RFP) for a design concept of a remotely piloted vehicle (RPV). The RPV designs were intended to simulate commercial transport aircraft within the model of 'Aeroworld.' The Aeroworld model was developed so that the RPV designs would be subject to many of the engineering problems and tradeoffs that dominate real-world commercial air transport designs, such as profitability, fuel efficiency, range vs. payload capabilities, and ease of production and maintenance. As part of the proposal, each team was required to construct a prototype and validate its design with a flight demonstration.

  18. PREFACE: International Conference on Quantum Simulators and Design, Hiroshima, Japan, 3 6 December 2006

    NASA Astrophysics Data System (ADS)

    Akai, Hisazumi; Oguchi, Tamio

    2007-09-01

    This special issue of Journal of Physics: Condensed Matter comprises selected papers from the 1st International Conference on Quantum Simulators and Design (QSD2006) held in Hiroshima, Japan, 3-6 December 2006. This conference was organized under the auspices of the Development of New Quantum Simulators and Quantum Design Grant-in-Aid for Scientific Research on Priority Areas, Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), and Hiroshima University Quantum design is a computational approach to the development of new materials with specified properties and functionalities. The basic ingredient is the use of quantum simulations to design a material that meets a given specification of properties and functionalities. For this to be successful, the quantum simulation should be highly reliable and be applicable to systems of realistic size. A central interest is, therefore, the development of new methods of quantum simulation and quantum design. This includes methods beyond the local density approximation of density functional theory (LDA), order-N methods, methods dealing with excitations and reactions, and so on, as well as the application of these methods to the design of new materials and devices. The field of quantum design has developed rapidly in the past few years and this conference provides an international forum for experimental and theoretical researchers to exchange ideas. A total of 183 delegates from 8 countries participated in the conference. There were 18 invited talks, 16 oral presentations and 100 posters. There were many new ideas and we foresee dramatic progress in the coming years. The 2nd International Conference on Quantum Simulators and Design will be held in Tokyo, Japan, 31 May-3 June 2008.

  19. Optimal design and uncertainty quantification in blood flow simulations for congenital heart disease

    NASA Astrophysics Data System (ADS)

    Marsden, Alison

    2009-11-01

    Recent work has demonstrated substantial progress in capabilities for patient-specific cardiovascular flow simulations. Recent advances include increasingly complex geometries, physiological flow conditions, and fluid structure interaction. However inputs to these simulations, including medical image data, catheter-derived pressures and material properties, can have significant uncertainties associated with them. For simulations to predict clinically useful and reliable output information, it is necessary to quantify the effects of input uncertainties on outputs of interest. In addition, blood flow simulation tools can now be efficiently coupled to shape optimization algorithms for surgery design applications, and these tools should incorporate uncertainty information. We present a unified framework to systematically and efficient account for uncertainties in simulations using adaptive stochastic collocation. In addition, we present a framework for derivative-free optimization of cardiovascular geometries, and layer these tools to perform optimization under uncertainty. These methods are demonstrated using simulations and surgery optimization to improve hemodynamics in pediatric cardiology applications.

  20. DEVELOPMENT OF NUCLEAR POWER PLANT SIMULATORS FOR SOVIET-DESIGNED NUCLEAR REACTORS.

    SciTech Connect

    Kohut, P.; Tutu, N.K.; Cleary, E.J.; Erickson, K.G.; Yoder, J.; Kroshilin, A.

    2001-01-07

    The US Department of Energy (US DOE), under the US government's International Nuclear Safety Program (INSP), is implementing a program of developing and providing simulators for many of the Russian and Ukrainian Nuclear Power Plants (NPPs). Pacific Northwest National Laboratory (PNNL) and Brookhaven National Laboratory (BNL) manage and provide technical oversight of the various INSP simulator projects for DOE. The program also includes a simulator technology transfer process to simulator design organizations in Russia and Ukraine. Training programs, installation of new simulators, and enhancements in existing simulators, are viewed as providing a relatively fast and cost-effective technology transfer that will result in measurable improvement in the safety culture and operation of NPPs. A review of this program, its present status, and its accomplishments are provided in this paper.

  1. Analysis of K-Ras Nuclear Expression in Fibroblasts and Mesangial Cells

    PubMed Central

    Fuentes-Calvo, Isabel; Blázquez-Medela, Ana M.; Santos, Eugenio; López-Novoa, José M.; Martínez-Salgado, Carlos

    2010-01-01

    Background Ras GTPases are considered cytoplasmic proteins that must be localized to cell membranes for activation, and there are few evidences of the presence of any Ras isoform in nuclei of eukaryotic cells. Methodology/Principal Findings Using conventional antibodies and inmunocytochemistry, differential centrifugation and western blot, we have observed the putative presence of K-Ras isoform in the nuclei of fibroblasts and mesangial cells. In order to avoid cross-reactions with other Ras isoforms, and using antibodies against K-Ras (R-3400, H3845-M01, sc-30) or pan-Ras (05-516, OP40) in cells that only expressed the K-Ras isoform (fibroblasts obtained from H-ras−/−,N-ras−/− mice) we also detected some nuclear positive expression. To further probe the identity of nuclear K-Ras, we have generated K-Ras knockout (K-ras−/−) embrionary fibroblasts by mating of K-ras+/− heterozygote mice. Using specific antibodies, only H- and N-Ras isoforms were observed in the cytoplasm of K-ras−/− fibroblasts. However, both K-Ras4A and K-Ras4B positive signals were detected by immunocytochemistry and Western blot with two commercial antibodies (sc-522 and sc-521 against each isoforms, respectively) in both cytoplasm and nuclei from K-ras−/− fibroblasts. Conclusions/Significance We show that the presence of K-Ras4B in fibroblast nuclei, already described by other authors, is probably due to a cross-reaction of the antibody with an undetermined nucleolar protein. Although this study also shows the possible nuclear expression of K-Ras isoform in fibroblasts or in mesangial cells, it also reveals the importance of being cautious in these studies about distribution of protein isoforms due to some important limitations imposed by the unspecificity of the antibodies or contaminations in cellular preparations. PMID:20090846

  2. Oncogenicity of human N-ras oncogene and proto-oncogene introduced into retroviral vectors

    SciTech Connect

    Souyri, M.; Vigon, I.; Charon, M.; Tambourin, P. )

    1989-09-01

    The N-ras gene is the only member of the ras family which has never been naturally transduced into a retrovirus. In order to study the in vitro and in vivo oncogenicity of N-ras and to compare its pathogenicity to that of H-ras, the authors have inserted an activated or a normal form of human N-ras cDNA into a slightly modified Harvey murine sarcoma virus-derived vector in which the H-ras p21 coding region had been deleted. The resulting constructions were transfected into NIH 3T3 cells. The activated N-ras-containing construct (HSN) induced 10{sup 4} foci per {mu}g of DNA and was found to be as transforming as H-ras was. After infection of the transfected cells by either the ecotropic Moloney murine leukemia virus or the amphotropic 4070A helper viruses, rescued transforming viruses were injected into newborn mice. Both pseudotypes of HSN virus containing activated N-ras induced the typical Harvey disease with similar latency. However, they found that the virus which contained normal N-ras p21 (HSn) was also pathogenic and induced splenomegaly, lymphadenopathies, and sarcoma in mice after a latency of 3 to 7 weeks. In addition, Moloney murine leukemia virus pseudotypes of N-ras caused neurological disorders in 30% of the infected animals. These results differed markedly from those of previous experiments in which the authors had inserted the activated form of N-ras in the pSV(X) vector: the resulting SVN-ras virus was transforming on NIH 3T3 cells but was poorly oncogenic in vivo. Altogether, these data demonstrated unequivocally that N-ras is potentially as oncogenic as H-ras and that such oncogenic effect could depend on the vector environment.

  3. Inhibition of Acid Sphingomyelinase Depletes Cellular Phosphatidylserine and Mislocalizes K-Ras from the Plasma Membrane.

    PubMed

    Cho, Kwang-Jin; van der Hoeven, Dharini; Zhou, Yong; Maekawa, Masashi; Ma, Xiaoping; Chen, Wei; Fairn, Gregory D; Hancock, John F

    2015-01-01

    K-Ras must localize to the plasma membrane for biological activity; thus, preventing plasma membrane interaction blocks K-Ras signal output. Here we show that inhibition of acid sphingomyelinase (ASM) mislocalizes both the K-Ras isoforms K-Ras4A and K-Ras4B from the plasma membrane to the endomembrane and inhibits their nanoclustering. We found that fendiline, a potent ASM inhibitor, reduces the phosphatidylserine (PtdSer) and cholesterol content of the inner plasma membrane. These lipid changes are causative because supplementation of fendiline-treated cells with exogenous PtdSer rapidly restores K-Ras4A and K-Ras4B plasma membrane binding, nanoclustering, and signal output. Conversely, supplementation with exogenous cholesterol restores K-Ras4A but not K-Ras4B nanoclustering. These experiments reveal different operational pools of PtdSer on the plasma membrane. Inhibition of ASM elevates cellular sphingomyelin and reduces cellular ceramide levels. Concordantly, delivery of recombinant ASM or exogenous ceramide to fendiline-treated cells rapidly relocalizes K-Ras4B and PtdSer to the plasma membrane. K-Ras4B mislocalization is also recapitulated in ASM-deficient Neimann-Pick type A and B fibroblasts. This study identifies sphingomyelin metabolism as an indirect regulator of K-Ras4A and K-Ras4B signaling through the control of PtdSer plasma membrane content. It also demonstrates the critical and selective importance of PtdSer to K-Ras4A and K-Ras4B plasma membrane binding and nanoscale spatial organization. PMID:26572827

  4. Inhibition of Acid Sphingomyelinase Depletes Cellular Phosphatidylserine and Mislocalizes K-Ras from the Plasma Membrane

    PubMed Central

    Cho, Kwang-jin; van der Hoeven, Dharini; Zhou, Yong; Maekawa, Masashi; Ma, Xiaoping; Chen, Wei

    2015-01-01

    K-Ras must localize to the plasma membrane for biological activity; thus, preventing plasma membrane interaction blocks K-Ras signal output. Here we show that inhibition of acid sphingomyelinase (ASM) mislocalizes both the K-Ras isoforms K-Ras4A and K-Ras4B from the plasma membrane to the endomembrane and inhibits their nanoclustering. We found that fendiline, a potent ASM inhibitor, reduces the phosphatidylserine (PtdSer) and cholesterol content of the inner plasma membrane. These lipid changes are causative because supplementation of fendiline-treated cells with exogenous PtdSer rapidly restores K-Ras4A and K-Ras4B plasma membrane binding, nanoclustering, and signal output. Conversely, supplementation with exogenous cholesterol restores K-Ras4A but not K-Ras4B nanoclustering. These experiments reveal different operational pools of PtdSer on the plasma membrane. Inhibition of ASM elevates cellular sphingomyelin and reduces cellular ceramide levels. Concordantly, delivery of recombinant ASM or exogenous ceramide to fendiline-treated cells rapidly relocalizes K-Ras4B and PtdSer to the plasma membrane. K-Ras4B mislocalization is also recapitulated in ASM-deficient Neimann-Pick type A and B fibroblasts. This study identifies sphingomyelin metabolism as an indirect regulator of K-Ras4A and K-Ras4B signaling through the control of PtdSer plasma membrane content. It also demonstrates the critical and selective importance of PtdSer to K-Ras4A and K-Ras4B plasma membrane binding and nanoscale spatial organization. PMID:26572827

  5. Phenotypic Screening Identifies Protein Synthesis Inhibitors as H-Ras-Nanocluster-Increasing Tumor Growth Inducers.

    PubMed

    Najumudeen, Arafath K; Posada, Itziar M D; Lectez, Benoit; Zhou, Yong; Landor, Sebastian K-J; Fallarero, Adyary; Vuorela, Pia; Hancock, John; Abankwa, Daniel

    2015-12-15

    Ras isoforms H-, N-, and K-ras are each mutated in specific cancer types at varying frequencies and have different activities in cell fate control. On the plasma membrane, Ras proteins are laterally segregated into isoform-specific nanoscale signaling hubs, termed nanoclusters. As Ras nanoclusters are required for Ras signaling, chemical modulators of nanoclusters represent ideal candidates for the specific modulation of Ras activity in cancer drug development. We therefore conducted a chemical screen with commercial and in-house natural product libraries using a cell-based H-ras-nanoclustering FRET assay. Next to established Ras inhibitors, such as a statin and farnesyl-transferase inhibitor, we surprisingly identified five protein synthesis inhibitors as positive regulators. Using commonly employed cycloheximide as a representative compound, we show that protein synthesis inhibition increased nanoclustering and effector recruitment specifically of active H-ras but not of K-ras. Consistent with these data, cycloheximide treatment activated both Erk and Akt kinases and specifically promoted H-rasG12V-induced, but not K-rasG12V-induced, PC12 cell differentiation. Intriguingly, cycloheximide increased the number of mammospheres, which are enriched for cancer stem cells. Depletion of H-ras in combination with cycloheximide significantly reduced mammosphere formation, suggesting an exquisite synthetic lethality. The potential of cycloheximide to promote tumor cell growth was also reflected in its ability to increase breast cancer cell tumors grown in ovo. These results illustrate the possibility of identifying Ras-isoform-specific modulators using nanocluster-directed screening. They also suggest an unexpected feedback from protein synthesis inhibition to Ras signaling, which might present a vulnerability in certain tumor cell types. PMID:26568031

  6. Targeting the K-Ras/PDEδ protein-protein interaction: the solution for Ras-driven cancers or just another therapeutic mirage?

    PubMed

    Frett, Brendan; Wang, Yuanxiang; Li, Hong-Yu

    2013-10-01

    The holy grail, finally? After years of unsuccessful attempts at drugging the Ras oncogene, a recent paper by Zimmerman et al. has revealed the possibility of inhibiting Ras signaling on a clinically relevant level by blocking the K-Ras/PDEδ protein-protein interaction. The results, reported in Nature, are highlighted herein with future implications and directions to evaluate the full clinical potential of this research. PMID:23939923

  7. The farnesyltransferase inhibitor, LB42708, inhibits growth and induces apoptosis irreversibly in H-ras and K-ras-transformed rat intestinal epithelial cells

    SciTech Connect

    Kim, Han-Soo; Kim, Ju Won; Gang, Jingu; Wen, Jing; Koh, Sang Seok; Koh, Jong Sung; Chung, Hyun-Ho; Song, Si Young . E-mail: gisong@yumc.yonsei.ac.kr

    2006-09-15

    LB42708 (LB7) and LB42908 (LB9) are pyrrole-based orally active farnesyltransferase inhibitors (FTIs) that have similar structures. The in vitro potencies of these compounds against FTase and GGTase I are remarkably similar, and yet they display different activity in apoptosis induction and morphological reversion of ras-transformed rat intestinal epithelial (RIE) cells. Both FTIs induced cell death despite K-ras prenylation, implying the participation of Ras-independent mechanism(s). Growth inhibition by these two FTIs was accompanied by G1 and G2/M cell cycle arrests in H-ras and K-ras-transformed RIE cells, respectively. We identified three key markers, p21{sup CIP1/WAF1}, RhoB and EGFR, that can explain the differences in the molecular mechanism of action between two FTIs. Only LB7 induced the upregulation of p21{sup CIP1/WAF1} and RhoB above the basal level that led to the cell cycle arrest and to distinct morphological alterations of ras-transformed RIE cells. Both FTIs successfully inhibited the ERK and activated JNK in RIE/K-ras cells. While the addition of conditioned medium from RIE/K-ras reversed the growth inhibition of ras-transformed RIE cells by LB9, it failed to overcome the growth inhibitory effect of LB7 in both H-ras- and K-ras-transformed RIE cells. We found that LB7, but not LB9, decreased the expression of EGFRs that confers the cellular unresponsiveness to EGFR ligands. These results suggest that LB7 causes the induction of p21{sup CIP1/WAF1} and RhoB and downregulation of EGFR that may serve as critical steps in the mechanism by which FTIs trigger irreversible inhibitions on the cell growth and apoptosis in ras-transformed cells.

  8. Cognitive task analysis-based design and authoring software for simulation training.

    PubMed

    Munro, Allen; Clark, Richard E

    2013-10-01

    The development of more effective medical simulators requires a collaborative team effort where three kinds of expertise are carefully coordinated: (1) exceptional medical expertise focused on providing complete and accurate information about the medical challenges (i.e., critical skills and knowledge) to be simulated; (2) instructional expertise focused on the design of simulation-based training and assessment methods that produce maximum learning and transfer to patient care; and (3) software development expertise that permits the efficient design and development of the software required to capture expertise, present it in an engaging way, and assess student interactions with the simulator. In this discussion, we describe a method of capturing more complete and accurate medical information for simulators and combine it with new instructional design strategies that emphasize the learning of complex knowledge. Finally, we describe three different types of software support (Development/Authoring, Run Time, and Post Run Time) required at different stages in the development of medical simulations and the instructional design elements of the software required at each stage. We describe the contributions expected of each kind of software and the different instructional control authoring support required. PMID:24084300

  9. Design for dependability: A simulation-based approach. Ph.D. Thesis, 1993

    NASA Technical Reports Server (NTRS)

    Goswami, Kumar K.

    1994-01-01

    This research addresses issues in simulation-based system level dependability analysis of fault-tolerant computer systems. The issues and difficulties of providing a general simulation-based approach for system level analysis are discussed and a methodology that address and tackle these issues is presented. The proposed methodology is designed to permit the study of a wide variety of architectures under various fault conditions. It permits detailed functional modeling of architectural features such as sparing policies, repair schemes, routing algorithms as well as other fault-tolerant mechanisms, and it allows the execution of actual application software. One key benefit of this approach is that the behavior of a system under faults does not have to be pre-defined as it is normally done. Instead, a system can be simulated in detail and injected with faults to determine its failure modes. The thesis describes how object-oriented design is used to incorporate this methodology into a general purpose design and fault injection package called DEPEND. A software model is presented that uses abstractions of application programs to study the behavior and effect of software on hardware faults in the early design stage when actual code is not available. Finally, an acceleration technique that combines hierarchical simulation, time acceleration algorithms and hybrid simulation to reduce simulation time is introduced.

  10. FEM design and simulation of a short, 10 MV, S-band Linac with Monte Carlo dose simulations

    SciTech Connect

    Baillie, Devin; Aubin, J. St.; Steciw, S.; Fallone, B. G.

    2015-04-15

    Purpose: Current commercial 10 MV Linac waveguides are 1.5 m. The authors’ current 6 MV linear accelerator–magnetic resonance imager (Linac–MR) system fits in typical radiotherapy vaults. To allow 10 MV treatments with the Linac–MR and still fit within typical vaults, the authors design a 10 MV Linac with an accelerator waveguide of the same length (27.5 cm) as current 6 MV Linacs. Methods: The first design stage is to design a cavity such that a specific experimental measurement for breakdown is applicable to the cavity. This is accomplished through the use of finite element method (FEM) simulations to match published shunt impedance, Q factor, and ratio of peak to mean-axial electric field strength from an electric breakdown study. A full waveguide is then designed and tuned in FEM simulations based on this cavity design. Electron trajectories are computed through the resulting radio frequency fields, and the waveguide geometry is modified by shifting the first coupling cavity in order to optimize the electron beam properties until the energy spread and mean energy closely match values published for an emulated 10 MV Linac. Finally, Monte Carlo dose simulations are used to compare the resulting photon beam depth dose profile and penumbra with that produced by the emulated 10 MV Linac. Results: The shunt impedance, Q factor, and ratio of peak to mean-axial electric field strength are all matched to within 0.1%. A first coupling cavity shift of 1.45 mm produces an energy spectrum width of 0.347 MeV, very close to the published value for the emulated 10 MV of 0.315 MeV, and a mean energy of 10.53 MeV, nearly identical to the published 10.5 MeV for the emulated 10 MV Linac. The depth dose profile produced by their new Linac is within 1% of that produced by the emulated 10 MV spectrum for all depths greater than 1.5 cm. The penumbra produced is 11% narrower, as measured from 80% to 20% of the central axis dose. Conclusions: The authors have successfully

  11. The inflammatory cytokine TNFα cooperates with Ras in elevating metastasis and turns WT-Ras to a tumor-promoting entity in MCF-7 cells

    PubMed Central

    2014-01-01

    Background In the present study we determined the relative contribution of two processes to breast cancer progression: (1) Intrinsic events, such as activation of the Ras pathway and down-regulation of p53; (2) The inflammatory cytokines TNFα and IL-1β, shown in our published studies to be highly expressed in tumors of >80% of breast cancer patients with recurrent disease. Methods Using MCF-7 human breast tumor cells originally expressing WT-Ras and WT-p53, we determined the impact of the above-mentioned elements and cooperativity between them on the expression of CXCL8 (ELISA, qRT-PCR), a member of a “cancer-related chemokine cluster” that we have previously identified. Then, we determined the mechanisms involved (Ras-binding-domain assays, Western blot, luciferase), and tested the impact of Ras + TNFα on angiogenicity (chorioallantoic membrane assays) and on tumor growth at the mammary fat pad of mice and on metastasis, in vivo. Results Using RasG12V that recapitulates multiple stimulations induced by receptor tyrosine kinases, we found that RasG12V alone induced CXCL8 expression at the mRNA and protein levels, whereas down-regulation of p53 did not. TNFα and IL-1β potently induced CXCL8 expression and synergized with RasG12V, together leading to amplified CXCL8 expression. Testing the impact of WT-Ras, which is the common form in breast cancer patients, we found that WT-Ras was not active in promoting CXCL8; however, TNFα has induced the activation of WT-Ras: joining these two elements has led to cooperative induction of CXCL8 expression, via the activation of MEK, NF-κB and AP-1. Importantly, TNFα has led to increased expression of WT-Ras in an active GTP-bound form, with properties similar to those of RasG12V. Jointly, TNFα + Ras activities have given rise to increased angiogenesis and to elevated tumor cell dissemination to lymph nodes. Conclusions TNFα cooperates with Ras in promoting the metastatic phenotype of MCF-7 breast tumor cells

  12. Function of RasGRP3 in the formation and progression of human breast cancer

    PubMed Central

    2014-01-01

    Introduction Ras guanine nucleotide exchange factors (RasGEFs) mediate the activation of the Ras signaling pathway that is over activated in many human cancers. The RasGRP3, an activator of H-Ras and R-Ras protein exerts oncogenic effects and the overexpression of the protein is observed in numerous malignant cancer types. Here, we investigated the putative alteration of expression and potential function of RasGRP3 in the formation and progression of human breast cancer. Methods The RasGRP3 and phosphoRasGRP3 expressions were examined in human invasive ductal adenocarcinoma derived samples and cell lines (BT-474, JIMT-1, MCF7, SK-BR-3, MDA-MB-453, T-47D) both in mRNA (Q-PCR) and protein (Western blot; immunohistochemistry) levels. To explore the biological function of the protein, RasGRP3 knockdown cultures were established. To assess the role of RasGRP3 in the viability of cells, annexin-V/PI staining and MitoProbe™ DilC1 (5) assay were performed. To clarify the function of the protein in cell proliferation and in the development of chemotherapeutic resistance, CyQuant assay was performed. To observe the RasGRP3 function in tumor formation, the Severe combined immunodeficiency (SCID) mouse model was used. To investigate the role of the protein in Ras-related signaling Q-PCR and Western blot experiments were performed. Results RasGRP3 expression was elevated in human breast tumor tissue samples as well as in multiple human breast cancer cell lines. Down-regulation of RasGRP3 expression in breast cancer cells decreased cell proliferation, induced apoptosis in MCF7 cells, and sensitized T-47D cells to the action of drugs Tamoxifen and trastuzumab (Herceptin). Gene silencing of RasGRP3 reduced tumor formation in mouse xenografts as well. Inhibition of RasGRP3 expression also reduced Akt, ERK1/2 and estrogen receptor alpha phosphorylation downstream from IGF-I insulin like growth factor-I (IGF-I) or epidermal growth factor (EGF) stimulation confirming the functional

  13. Targeting the RAS pathway by mitogen-activated protein kinase inhibitors.

    PubMed

    Kiessling, Michael K; Rogler, Gerhard

    2015-01-01

    Targeting of oncogenic driver mutations with small-molecule inhibitors resulted in powerful treatment options for cancer patients in recent years. The RAS (rat sarcoma) pathway is among the most frequently mutated pathways in human cancer. Whereas targeting mutant Kirsten RAS (KRAS) remains difficult, mutant B rapidly accelerated fibrosarcoma (BRAF) kinase is an established drug target in cancer. Now data show that neuroblastoma RAS (NRAS) and even Harvey RAS (HRAS) mutations could be predictive markers for treatment with mitogen-activated protein kinase (MEK) inhibitors. This review discusses recent preclinical and clinical studies of MEK inhibitors in BRAF and RAS mutant cancer. PMID:26691679

  14. The use of vestibular models for design and evaluation of flight simulator motion

    NASA Technical Reports Server (NTRS)

    Bussolari, Steven R.; Young, Laurence R.; Lee, Alfred T.

    1989-01-01

    Quantitative models for the dynamics of the human vestibular system are applied to the design and evaluation of flight simulator platform motion. An optimal simulator motion control algorithm is generated to minimize the vector difference between perceived spatial orientation estimated in flight and in simulation. The motion controller has been implemented on the Vertical Motion Simulator at NASA Ames Research Center and evaluated experimentally through measurement of pilot performance and subjective rating during VTOL aircraft simulation. In general, pilot performance in a longitudinal tracking task (formation flight) did not appear to be sensitive to variations in platform motion condition as long as motion was present. However, pilot assessment of motion fidelity by means of a rating scale designed for this purpose, were sensitive to motion controller design. Platform motion generated with the optimal motion controller was found to be generally equivalent to that generated by conventional linear crossfeed washout. The vestibular models are used to evaluate the motion fidelity of transport category aircraft (Boeing 727) simulation in a pilot performance and simulator acceptability study at the Man-Vehicle Systems Research Facility at NASA Ames Research Center. Eighteen airline pilots, currently flying B-727, were given a series of flight scenarios in the simulator under various conditions of simulator motion. The scenarios were chosen to reflect the flight maneuvers that these pilots might expect to be given during a routine pilot proficiency check. Pilot performance and subjective rating of simulator fidelity was relatively insensitive to the motion condition, despite large differences in the amplitude of motion provided. This lack of sensitivity may be explained by means of the vestibular models, which predict little difference in the modeled motion sensations of the pilots when different motion conditions are imposed.

  15. Analyzing the influence of median cross-section design on highway safety using vehicle dynamics simulations.

    PubMed

    Stine, Jason S; Hamblin, Bridget C; Brennan, Sean N; Donnell, Eric T

    2010-11-01

    Although vehicle dynamics simulations have long been used in vehicle design and crash reconstruction, their use for highway design is rare. This paper investigates the safety of highway medians through iterative simulations of off-road median encroachments. The commercially available software CarSim was used to simulate over one hundred thousand encroachments, representing the entire passenger vehicle fleet and a wide range of encroachment angles, departure speeds, steering inputs, and braking inputs. Each individual simulation output was then weighted using data from previous studies to reflect the probability of each specific accident scenario occurring in a real-life median encroachment. Results of this analysis illustrate the relative influence of median cross-section geometry on the resulting accident outcomes. The simulations indicate that the overall safety of a highway median depends on the occurrence of both vehicle rollover and median crossover events, and the cross-section shape, slope, and width are all shown to greatly affect each of these incidents. An evaluation of the simulation results was conducted with vehicle trajectories from previous experimental crash tests. Further assessment of the aggregate simulation results to actual crash data was achieved through comparison with several databases of crash statistics. Both efforts showed a strong agreement between the simulations and the real-life crash data. PMID:20728628

  16. Efforts in developing design and simulation tools for MEMS: DS/MEMS and CA/MEMS

    NASA Astrophysics Data System (ADS)

    Youn, Sung Kie; Kwak, Byung M.; Kwon, Jang-Hyuk; Chang, Su-Young; Huh, Jae S.; Kim, Eugene

    2002-04-01

    In this work, multi-physics simulation software (CA/MEMS) and design-optimization software (DS/MEMS) tailored for MEMS devices are introduced. The CA/MEMS, which is a simulation engine for DS/MEMS, is a 3-D multi-physics analysis code utilizing various numerical methods such as FEM, BEM and FVM to efficiently model MEMS application problems. The current CA/MEMS includes analysis- modules for structural, thermal, electric, electromagnetic and fluidic fields and is capable of the analyses of various coupled- field problems for MEMS applications. DS/MEMS is design optimization engine for MEMS devices. With integrating CA/MEMS and pre/post processor into CAD environment, DS/MEMS is organized to work in parametric CAD platform. DS/MEMS consists of optimal design module and robust design module. The optimal design module provides users three methods nonlinear programming, Taguchi parameter design and the response surface method. The robust design module, which is specially developed for MEMS application, can be used to minimize the perturbation of performances of MEMS devices under uncertainties of MEMS devices, such as process tolerance and the change of operating environments. To verify the efficiency and accuracy of CA/MEMS and the practical usefulness of DS/MEMS, we have been comparing the simulated results of CA/MEMS with those of other commercial codes and experimental data of manufactured MEMS devices, and investigating the performances of the optimized designs through DS/MEMS.

  17. CaM interaction and Ser181 phosphorylation as new K-Ras signaling modulators

    PubMed Central

    Alvarez-Moya, Blanca; Barceló, Carles; Tebar, Francesc; Jaumot, Montserrat

    2011-01-01

    The small G-protein Ras was the first oncogene to be identified and has a very important contribution to human cancer development (20–23% prevalence). K-RasB, one of the members of the Ras family, is the one that is most mutated and plays a prominent role in pancreatic, colon and lung cancer development. Ras proteins are membrane bound GTPases that cycle between inactive, GDP-bound and active, GTP-bound, states. Most of the research into K-RasB activity regulation has focused on the analysis of how GTP-exchange factors (GEFs) and GTPase activating proteins (GAPs) are regulated by external and internal signals. In contrast, oncogenic K-RasB has a very low GTPase activity and furthermore is not deactivated by GAPs. Consequently, the consensus was that activity of oncogenic K-RasB was not modulated. In this extra view we recapitulate some recent data showing that calmodulin binding to K-RasB inhibits phosphorylation of K-RasB at Ser181, near to the membrane anchoring domain, modulating signaling of both non-oncogenic and oncogenic K-RasB. This may be relevant to normal cell physiology, but also opens new therapeutic perspectives for the inhibition of oncogenic K-RasB signaling in tumors. PMID:21776410

  18. RasGRP1 Transgenic Mice Develop Cutaneous Squamous Cell Carcinomas in Response to Skin Wounding

    PubMed Central

    Diez, Federico R.; Garrido, Ann A.; Sharma, Amrish; Luke, Courtney T.; Stone, James C.; Dower, Nancy A.; Cline, J. Mark; Lorenzo, Patricia S.

    2009-01-01

    Models of epidermal carcinogenesis have demonstrated that Ras is a critical molecule involved in tumor initiation and progression. Previously, we have shown that RasGRP1 increases the susceptibility of mice to skin tumorigenesis when overexpressed in the epidermis by a transgenic approach, related to its ability to activate Ras. Moreover, RasGRP1 transgenic mice develop spontaneous papillomas and cutaneous squamous cell carcinomas, some of which appear to originate in sites of injury, suggesting that RasGRP1 may be responding to signals generated during the wound-healing process. In this study, we examined the response of the RasGRP1 transgenic animals to full-thickness incision wounding of the skin, and demonstrated that they respond by developing tumors along the wounded site. The tumors did not present mutations in the H-ras gene, but Rasgrp1 transgene dosage correlated with tumor susceptibility and size. Analysis of serum cytokines showed increased levels of granulocyte colony-stimulating factor in transgenic animals after wounding. Furthermore, in vitro experiments with primary keratinocytes showed that granulocyte colony-stimulating factor stimulated Ras activation, although RasGRP1 was dispensable for this effect. Since granulocyte colony-stimulating factor has been recently associated with proliferation of skin cancer cells, our results may help in the elucidation of pathways that activate Ras in the epidermis during tumorigenesis in the absence of oncogenic ras mutations. PMID:19497993

  19. High resolution simulations of ignition capsule designs for the National Ignition Facility

    SciTech Connect

    Clark, D S; Haan, S W; Cook, A W; Edwards, M J; Hammel, B A; Koning, J M; Marinak, M M

    2011-02-17

    Ignition capsule designs for the National Ignition Facility (NIF) [G. H. Miller, E. I. Moses, and C. R. Wuest, Opt. Eng. 443, 2841 (2004)] have continued to evolve in light of improved physical data inputs, improving simulation techniques, and - most recently - experimental data from a growing number of NIF sub-ignition experiments. This paper summarizes a number of recent changes to the cryogenic capsule design and some of our latest techniques in simulating its performance. Specifically, recent experimental results indicated harder x-ray drive spectra in NIF hohlraums than were predicted and used in previous capsule optimization studies. To accommodate this harder drive spectrum, a series of high-resolution 2-D simulations, resolving Legendre mode numbers as high as two thousand, were run and the germanium dopant concentration and ablator shell thicknesses re-optimized accordingly. Simultaneously, the possibility of cooperative or nonlinear interaction between neighboring ablator surface defects has motivated a series of fully 3-D simulations run with the massively parallel HYDRA code. These last simulations include perturbations seeded on all capsule interfaces and can use actual measured shell surfaces as initial conditions. 3-D simulations resolving Legendre modes up to two hundred on large capsule sectors have run through ignition and burn, and higher resolution simulations resolving as high as mode twelve hundred have been run to benchmark high-resolution 2-D runs. Finally, highly resolved 3-D simulations have also been run of the jet-type perturbation caused by the fill tube fitted to the capsule. These 3-D simulations compare well with the more typical 2-D simulations used in assessing the fill tube's impact on ignition. Coupled with the latest experimental inputs from NIF, our improving simulation capability yields a fuller and more accurate picture of NIF ignition capsule performance.

  20. IB: a Monte Carlo Simulation Tool for Neutron Scattering Instrument Design under Parallel Virtual Machine

    SciTech Connect

    Zhao, Jinkui

    2011-01-01

    IB is a Monte Carlo simulation tool for aiding neutron scattering instrument designs. It is written in C++ and implemented under Parallel Virtual Machine. The program has a few basic components, or modules, that can be used to build a virtual neutron scattering instrument. More complex components, such as neutron guides and multichannel beam benders, can be constructed using the grouping technique unique to IB. Users can specify a collection of modules as a group. For example, a neutron guide can be constructed by grouping four neutron mirrors together that make up the four sides of the guide. IB s simulation engine ensures that neutrons entering a group will be properly operated upon by all members of the group. For simulations that require higher computer speed, the program can be run in parallel mode under the PVM architecture. Initially, the program was written for designing instruments on pulsed neutron sources, it has since been used to simulate reactor based instruments as well.